Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

GABAergic dysfunction in mood disorders


The authors review the available literature on the preclinical and clinical studies involving GABAergic neurotransmission in mood disorders. γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter present almost exclusively in the central nervous system (CNS), distributed across almost all brain regions, and expressed in interneurons modulating local circuits. The role of GABAergic dysfunction in mood disorders was first proposed 20 years ago. Preclinical studies have suggested that GABA levels may be decreased in animal models of depression, and clinical studies reported low plasma and CSF GABA levels in mood disorder patients. Also, antidepressants, mood stabilizers, electroconvulsive therapy, and GABA agonists have been shown to reverse the depression-like behavior in animal models and to be effective in unipolar and bipolar patients by increasing brain GABAergic activity. The hypothesis of reduced GABAergic activity in mood disorders may complement the monoaminergic and serotonergic theories, proposing that the balance between multiple neurotransmitter systems may be altered in these disorders. However, low GABAergic cortical function may probably be a feature of a subset of mood disorder patients, representing a genetic susceptibility. In this paper, we discuss the status of GABAergic hypothesis of mood disorders and suggest possible directions for future preclinical and clinical research in this area.


γ-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the mammalian brain, where it is widely distributed.1 In regions such as the cerebral cortex, hippocampus, thalamus, basal ganglia, cerebellum, hypothalamus, and brainstem, it represents about one-third of the synapses.2,3,4 GABA transmission is present in interneurons modulating local neuronal circuitry, including noradrenergic, dopaminergic, and serotonergic neurons.

The potential role of GABAergic dysfunction in mood disorders was first proposed by Emrich et al,5 based on the efficacy of valproate in the treatment of bipolar patients. They proposed that valproate, through the enhancement of GABA brain concentration, might compensate for a potential GABAergic deficiency, and formulated the GABA hypothesis of mood disorders. After Emrich's hypothesis, several animal and human studies have evaluated the potential role of GABAergic abnormalities in the pathophysiology of mood disorders.6

In the present paper, we reviewed the physiology of GABAergic transmission in human brain and summarized the findings from preclinical and clinical studies evaluating GABAergic function in mood disorders. We attempted to elucidate available findings for GABAergic dysfunction in an integrated hypothesis of mood disorder and also discussed potential directions for future research in this area.

GABAergic pathways in the brain

GABA metabolism and uptake

GABA in GABAergic terminals is formed from glutamate in an enzymatic reaction mediated by glutamic acid decarboxylase (GAD), using pyridoxal phosphate as cofactor.7,8 After being released into the synapses, GABA is inactivated by reuptake into presynaptic terminals or into glia cells mediated by GABA transporters (GATs).9 Specifically, at the present time, four complementary DNAs (cDNAs) encoding highly homologous GATs proteins have been cloned (GAT-1, GAT-2, GAT-3, and BGT-1). GAT-1 is considered to be a neuronal transporter, GAT-2 and GAT-3 are believed to be glial transporters, whereas the role of BGT-1 in brain GABA uptake is unknown.10 Precisely, GAT-1 is the most copiously expressed GAT in the CNS and is mainly localized into presynaptic axon terminal and into few astrocytic processes. GAT-2 is primarily present in the leptomeninges and in ependymal and choroid plexus cells and, to a minor extent, in neuronal and non-neuronal elements. GAT-3 is localized exclusively to distal astrocytic processes, although a neuronal localization has been reported in some brain regions such as the retina.10 GATs are regulated by several factors including GABA itself, brain-derived neurotrophic factor (BDNF), and hormones. The different response of GATs to the composition of extracellular environment, the different regulation of their activity and/or expression, and the possibility of reversing the direction of GABA transport, confer to the GABA transport system considerable flexibility for the fine regulation of GABA levels under physiological and pathological conditions.11

GABA that is taken up by astrocytes is not immediately available for synaptic transmission, because it is metabolized to succinic semialdehyde (SSA) by GABA-transaminase (GABA-T), which uses pyridoxal phosphate. Then, succinic semialdehyde is oxidized either by succinic semialdehyde dehydrogenase (SSA-DH) to succinic acid (SA), which re-enters the Kreb's cycle and then is transformed into glutamate, or by aldehyde reductase to γ-hydroxybutyrate. Glutamate in astrocytes cannot be converted into GABA due to the absence of GAD and is transformed by glutamine synthetase into glutamine, which is then transferred to axon terminals by specific transporters. In nerve terminals, glutamine is then converted into glutamate by the enzyme glutaminase, and, finally, GAD forms GABA from glutamate closing the cycle7,8 (Figure 1). On the contrary, GABA that is taken up by neuronal transporters is readily available for further release, because it either undergoes the same transformation as in astrocytes (with the notable difference that nerve endings contain GAD and can resynthesize GABA) or is recycled directly into synaptic vesicles. GAD is localized only in GABAergic presynaptic terminals, lacks in glial cells, and two forms have been discovered so far (GAD65 and GAD67).12 Glutamine synthetase is present only in glia, whereas GABA-T and SSA-DH are found in neuronal and glial mitochondria.4

Figure 1

GABA metabolism and uptake in human brain. Glutamate is the precursor of free GABA in GABAergic terminals and comes from two different sources (Kreb's cycle in glia cells and glutamine in nerve terminals). Then the enzyme glutamic acid decarboxylase (GAD) forms GABA from glutamate. After being released into the synapses, GABA is inactivated by reuptake mediated by GABA transporters (GATs) into presynaptic terminals or into glia cells where it is metabolized by GABA transaminase (GABA-T).

GABA receptors

GABAergic receptors are composed by two main types with different distribution on the surface of neurons, GABAA and GABAB receptors.

GABAA receptors are ionotropic and mostly postsynaptic receptors mainly located at the apical dendrite of the neurons, causing the fast inhibitory postsynaptic potential (IPSP).13 They are hetero-oligomeric membrane proteins organized in a channel, composed of five subunits belonging to several different classes with multiple variants (α1–α6; β1–β4, γ1–γ3, δ, ɛ, θ, π, and ρ1–ρ3).14 Each subunit has a large N terminus, four hydrophobic transmembrane domains, an intracellular loop containing protein kinase A, protein kinase C, and tyrosine kinase phosphorylation sites, and a short C terminus. GABAA receptor usually contains α, β, and γ subunits with variable combinations, which may be relevant to pharmacological differences observed between drugs and may modulate receptor activity. In mammalian brain, α1β2γ2 is the major GABAA receptor subunit. During neurotransmission, GABA acts postsynaptically through allosteric interaction with GABAA receptors and allows the chloride (Cl) ion channel opening, increasing the conductance of Cl15,16. Once GABAA receptors are activated, hyperpolarization of the neuronal membrane is established, reducing the cell excitability and leading to the inhibitory actions of GABA. However, in the presence of chronic GABA administration, Cl currents gradually decrease, as per a concentration-dependent GABAA response. GABAA receptors have several binding sites for different ligands, such as muscimol (GABA agonist), bicuculline (GABA antagonist), benzodiazepines (BZDs), barbiturates, ethanol, anticonvulsants, neurosteroids, steroid anesthetics, and volatile general anesthetics.17,18,19 These are allosteric agents, leading to increased GABA affinity and increased frequency of chloride channel opening. Specifically, BZDs bind to subunit α and increase the affinity of the receptor for GABA.20,21 In addition, it has been shown that phosphorylation and dephosphorylation processes might regulate GABAA receptor function. For instance, it has been reported that in specific brain cells, both protein kinase A (PKA) and C (PKC) modulate the minimal inhibitory postsynaptic currents.11 Moreover, it has been reported that zinc, a divalent cation that is known to regulate synaptic excitation, inhibits GABA-mediated responses through an interaction with histidine residues on the GABAA receptor complex. Probably, the sensitivity of GABAA receptors to zinc may be enhanced or reduced in the presence of the subunit α6 or γ2, respectively.11 Furthermore, growing evidence has demonstrated that GABAergic transmission can be potentiated via neurosteroids by interaction with GABAA receptors, particularly the α and δ subunits.11 GABAB receptors were initially shown to be autoreceptors or heteroreceptors regulating GABA or other neurotransmissions, unrelated to the chloride ionophores, basically by suppressing neuronal calcium conductance. They are mainly located on presynaptic terminal soma and mediate the slow IPSP.13 However, subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K+ conductance and associated neuronal hyperpolarization.22 They are metabotropic receptors coupled to Gi or G0 protein, which respectively lead to activation or to inhibition of neurotransmitter release, and may modulate cAMP accumulation.23 They are not linked to the BDZs recognition sites and their structures are less well characterized than GABAA receptors. Baclofen is a highly selective agonist for GABAB receptors.

GABAergic modulation of neuronal activity

Animal studies reported that GABA decreases dopamine firing in subcortical and mesocortical areas,24,25,26 and that GABAergic interneurons have extensive interaction with dopaminergic axons in rat medial prefrontal cortex.27 Functional studies reported that the administration of vigabatrin, which increases brain GABA levels, inhibiting GABA-T, decreased the mesocortical dopamine release in mammalian animals28,29 and decreased D2 receptors binding in human basal ganglia.30 However, GABA may also activate the dopaminergic system, depending upon the brain region and the duration of GABA stimulation.31 It has indeed been reported that muscimol, which is a GABA agonist, may reduce the immobility time in the behavioral despair model for depression by activating the rat dopaminergic system,32 and that GABA may enhance dopamine release in rat striatum and frontal cortex.33 In turn, dopamine modulates GABAergic inhibition in several rat brain regions (striatum, globus pallidus, and prefrontal cortex), through a synergism between dopaminergic receptors.34,35,36 Although this mechanism is still presently unclear, it is likely that D1 receptor activation would lead to an increase of GABA release, whereas D2 receptor activation would inhibit this release.37,38 An important clue of the involvement of dopamine receptors in the regulation of GABA transmission comes from the studies showing that D4 receptor, which is expressed at the highest level in GABAergic neurons, modulates GABAergic signaling in prefrontal cortex.39 In particular, it was reported that activation of D4 receptors in prefrontal cortex pyramidal neurons inhibits GABAA channel functions by regulating the PKA/protein phosphatase signaling complex.

It is fascinating to note, albeit not surprising, that in specific brain areas, the complex crosstalk between GABA and dopamine is also modulated by glutamate. In a very elegant investigation, Cobb and Abercrombie40 have reported the role of GABA and glutamate receptors in the regulation of dendritic dopamine release under normal conditions and in response to systemic haloperidol administration (ie via intraperitoneal injection). They found that nigral dopamine release in the intact ganglia appears to be subject to strong regulation by GABA afferents, with little or no apparent influence of glutamate neurotransmission. When dopamine neurotransmission in this circuitry is impaired by systemic haloperidol administration, excitatory effects of glutamate on dendritic dopamine efflux supercede the tonic inhibition by GABA, and increases in nigral dopamine release occur.

Animal studies reported a complex interaction between GABAergic and noradrenergic transmissions. It has been reported that GABA, progabide, and fengabine induce norepinephrine neuronal activity in rat brains.41,42,43,44 GABAA and GABAB receptor activation may, respectively, increase and decrease norepinephrine release in rat cortex and hippocampus,45,46,47 whereas baclofen reduced adrenergic binding sites.48 Also, norepinephrine increased GABA inhibitory transmission in human cerebral cortex, probably via α-adrenergic receptors,49 and in rat cerebellar cortex.50

GABA seems to decrease serotonergic transmission. GABA agonists, such as muscimol, or progabide, and diproxylacetamide, a GABA-T inhibitor, appeared to reduce the utilization rate and the synthesis of serotonin in rat brains,43,51,52,53 probably through GABA receptors located in the raphé nuclei.53 However, the GABA-serotonin relationship may be more complex. It has indeed been reported that serotonin release is increased by stimulation of GABA receptors in rat suprachiasmatic areas.54 Also, it has been shown that GABAA/B and 5-HT1A/B agonists decrease serotonin and GABA release in rat raphé nuclei,55 suggesting a reciprocal innervation between GABAergic and serotonergic neurons. Moreover, 5-HT2A/C receptors activate synaptic activity of GABAergic interneurons in rat hippocampus, prefrontal cortex, and dorsal raphe nucleus.56,57,58 Precisely, serotonin may induce GABA inhibitory inputs to serotonergic neurons of the dorsal raphé nucleus via 5-HT2A/C receptors in a negative feedback loop.58 Furthermore, progabide, baclofen, valproate, and diazepam may increase 5-HT2 induced head-twitch and 5-HT2 receptors in rat frontal cortex.59,60,61 It is interesting to note that GABAA receptor composition and level were reduced in amygdala and hippocampus of mice with inactivated 5HT1 receptors.62

Several studies have suggested that steroid hormones are involved in the regulation of the brain physiology as well as in the pathophysiology of many neuropsychiatric disorders by modulating GABAergic neurotransmission.63,64,65 This concept was further supported, during the last decade, by studies reporting a link between GABA system and neurosteroids, which are a group of steroids synthesized de novo in the nervous system from sterol precursors.66 Steroidogenesis occurs in glial and neuronal cells, when cholesterol is transported into the mitochondrion, and then it is converted to pregnenolone by the P450 side-chain cleavage enzyme. In turn, pregnenolone can be metabolized to pregnanes (pregnenolone sulfate, pregnanolone, allopregnanolone) and androstanes (dehydroepiandrosterone, dehydroepiandrosterone-sulfate, dihydrotestoterone metabolites).66 Although the mechanisms involved in the regulation of neurosteroids within the cells are still largely unknown, Do-Rego et al 67 have recently reported that GABA itself, acting through GABAA receptors, inhibits the activity of neurosteroidogenic enzymes. The effects of neurosteroids on GABAA receptors have been extensively investigated. An overall assessment of such investigations reveals that pregnanes and androstanes can generally be considered, respectively, positive and negative allosteric modulators of GABAA receptors.66,68,69 In addition to these nongenomic effects, it has been reported that neurosteroids have the ability to modulate GABAA receptors with an indirect genomic mechanism.66

Although in this review we mention the complex relationship of GABA with those neurotransmitters commonly involved in mood disorders, with an eye toward the available literature, we can say that GABA modulates or can be modulated by almost all neurotransmitters and neuromodulators present in the CNS. Thus, it should be mentioned that the precise knowledge of the relationship of GABA with other neurotransmitters will reveal new and perhaps unexpected aspects of how and why GABA could be involved in affective disorders.

GABA and the pathophysiology of mood disorders

Preclinical studies (Table 1)

Table 1 Clinical studies on GABA

The available animal models attempt to mimic the human brain and behavioral dysfunction that may be present in mood disorders, such as depressed mood, psychomotor retardation, and cognitive deficits.

Behavioral despair model

After vigorously swimming for a few minutes, a rat forced to swim in a cylinder of water, where it cannot escape, assumes an immobile posture, which reflects a lowered mood state. This reaction is sensitive to tricyclic antidepressants and electroconvulsive shock therapy (ECST), but not to anxiolytic or major tranquilizers.70,71 Reduced GABA levels in rat nucleus accumbens, brain stem, and cortex have been reported after a session of forced swimming test.72 Also, muscimol, a GABA agonist, reduced the immobility, whereas picrotoxin, a GABA antagonist, reduced the muscimol-induced reduction of the immobility.73

Learned helplessness model

After suffering from an inescapable foot shock, animals are not able to perform simple escape tasks in a shuttle box,74 resembling the psychomotor retardation present in human depression. Sherman and Petty75 demonstrated that GABA injection into frontal neocortex and hippocampus reversed the learned helplessness reaction. Also, a learned helplessness behavior has been produced in naïve nonstressed rats with the intrahippocampal injection of bicuculline, a competitive GABAA receptor antagonist.75 The same authors reported that the GABA release in hippocampus is decreased in parallel with the development of behavioral abnormality, and reversed by imipramine, but not by neuroleptics.76,77 Moreover, the chronic administration of muscimol or progabide reversed the learned helplessness behavior,73,78 whereas picrotoxine, a GABA antagonist, abolished the mucimol-induced reversal of helplessness behavior.73 Furthermore, GABAA receptors have also been found to be downregulated in the frontal cortex, hippocampus, and striatum of rats exposed to the learned helplessness paradigm.79 GABAB neurotransmission also seems to be involved in learned helplessness behavior, as baclofen, a GABAB receptor agonist, attenuated the behavioral deficit-restoring effect of antidepressants.80,81 Anti-depressants, such as imipramine and desipramine, have been shown to improve the learned helplessness behavior in rats.77,81,82 Interestingly, Plaznik et al 83 suggested that, besides decreased GABAergic activity, also noradrenergic, serotoninergic, and dopaminergic hypoactivity, and catecholaminergic hyperactivity contribute to the helplessness behavior. Also, adrenergic blockers, such as prazosin and penbutolol, diminished the reversal of depressive-like behavior by muscimol and imipramine-like drugs,73 suggesting that noradrenergic receptors may play an important role in the antidepressant-like profile of GABA agonists.

It has also been suggested that pretreatment with anxiogenic BDZ receptor ligands induces learned helplessness.84,85,86

Olfactory bulbectomy model

Rats that have had their olfactory bulbs removed show increase in locomotor activity, deficits in memory, changes in food-motivated behavior, and a pervasive deficit in passive-avoidance learning.87 After olfactory bulbectomy, GABA turnover was reported to be increased in rat amygdaloid cortex.88 GABAB receptor binding in frontal cortex, but not in other brain regions, has been found to be decreased about 50% in this model,89,90 whereas GABAA receptor binding increased in frontal cortex and, transiently, in hippocampus in rats.90 Desipramine reversed the behavioral deficit in rats with olfactory bulbectomy, increasing the frontal cortex GABAB receptor density.91 It has also been showed that baclofen,92 progabide,78 and fengabine93 reverse the behavioral deficit in this model.

Summing up, the findings from available preclinical models are fairly consistent with a GABA transmission deficit, especially in frontal cortex and hippocampus. With regard to mania, no animal models that examined GABAergic neurotransmission have been developed so far.

Clinical studies (Table 1)

CSF studies

CSF GABA may originate from brain and reflect GABAergic brain activity.94,95 Lower CSF GABA levels have been found in unipolar96,97,98,99,100 and bipolar patients98 compared to controls (Table 1). However, several studies showed no abnormalities in GABA CSF levels in unipolar101 and, especially, bipolar patients.100,101,102,103 Discrepancies between positive and negative studies may be in part explained by methodological differences, such as the aliquot of CSF examined, and the subject characteristics (ie. age, gender, mood), particularly in the reports involving bipolar patients.102,103

Plasma studies GABA plasma levels have been proposed as an index of brain GABA activity, probably being of central origin.104,105 Plasma and brain GABA levels change in similar proportion after pharmacological manipulations.106,107,108,109,110 Also, a correlation between CSF and plasma GABA levels has been found in animals,107,111 and humans,112 but not in all studies.113,114,115

Regarding mood disorder patients, plasma GABA levels have been found to be lower in about 40% of depressed, manic, and euthymic subjects.98,116,117,118,119,120 Low GABA plasma levels persist after recovey from depression, or after treatment with antidepressants, for example desipramine,116,117,118,119,120,121 and it is not correlated with the severity of depression.118 Also, plasma GABA levels remained stable after 4 years of follow-up in unipolar patients, independently of clinical state,122 while no follow-up studies of GABA plasma levels have been conducted in bipolar patients. Furthermore, GABA plasma levels have found to be low in children and adolescents with mood disorders.123 Moreover, GABA plasma level has been reported to be a relatively stable biological marker even in healthy individuals, being independent of activity, diet, gender, menstrual cycle, and circadian fluctuations.104,115,124,125,126

Additional evidence in support of a GABA deficit in mood disorder patients are the findings of lower platelet GABA-T and plasma GAD activities reported in unipolar and bipolar patients.127,128 Furthermore, dysphoria and mood disturbances were reported in euthymic bipolar and normal individuals after intravenous GABA administration.129 Interestingly, higher plasma GABA levels have been reported to correlate with clinical response to electroconvulsive therapy (ECT) in depressed patients130 and to valproate in manic patients,131 possibly suggesting that the affective patients with least abnormal GABA levels may have superior response. However, Rode et al,132 did not find any significant difference between depressed patients and healthy controls for plasma GABA levels. Low plasma GABA levels have also been found in alcohol dependence133 and in premenstrual dysphoric disorder,134,135 which have been reported to be related to mood disorders.134,136 In other major psychiatric disorders, such as schizophrenia,99 panic disorder,137 or anorexia nervosa,99,138 no low plasma GABA or CSF levels have been reported. These findings taken together demonstrate some specificity of low GABA levels for mood disorders. An important limitation to the available findings of peripheral abnormalities is that it is not known whether they reflect in vivo brain measures of GABAergic neurotransmission.

The available studies suggest that low plasma GABA levels may be a peripheral trait-like marker, at least in a subset of unipolar104,124 and bipolar patients,98,120 paralleling low CSF GABA findings in affective patients. To this regard, it is interesting to note that it has recently been shown that plasma GABA levels in first-degree relatives of patients with major depressive disorder were significantly lower compared to those with no family history of psychiatric illness, suggesting that the GABA plasma level is under genetic control.139 This study would sustain that low GABA levels may be specific for a subgroup of mood disorder patients, perhaps those with a family history of mood disorder.116

Post-mortem studies

GAD brain activity has been found to be reduced in depressed unipolar patients compared to controls in several brain regions, such as frontal cortex, occipital cortex, and basal ganglia.140 GABAA receptor binding sites have been found to be abnormally increased in frontal cortex of depressed suicide victims,141 suggesting lowered GABAergic activity in those patients. However, no significant differences between suicide victims and nonpsychiatric controls for GABAA and GABAB receptor binding sites,142,143,144,145 GAD activity,141 and GABA concentration146 have been found in several brain areas. Recently, support for abnormally decreased GABAergic neurotransmission in anterior cingulate, prefrontal cortex, and hippocampus in bipolar, but not unipolar disorder patients has been reported by several postmortem studies, as shown by decreased expression of GAD65 and GAD67 and decreased density of GABAergic neurons.147,148,149,150 These post-mortem studies together sustain the hypothesis of low GABA brain activity in mood disorder patients, but not in suicide victims.

Intriguingly, Honig et al 151 reported a negative correlation between GABA levels in bilateral frontal lobes and depression severity in refractory depressed bipolar or unipolar in-patients admitted for psychosurgery.

Neuroimaging studies

A recent SPECT study reported abnormally decreased GABAA receptor density in the prefrontal cortex of mood disorder patients, mainly bipolar, with or without akinetic catatonia,152 a psychomotor syndrome that can be seen in mood disorders and responsive to lorazepam. Recently, a controlled MRS study found abnormally reduced GABA levels in occipital cortex of drug-free depressed patients, without correlation with severity of depression,153 with a possible normalization after 2 months of selective serotonin reuptake inhibitor (SSRI) treatment.154 Although the occipital lobe has not been extensively evaluated in mood disorder patients, these findings are quite interesting, as they report for the first time low in vivo GABA levels in depressed patients. Abnormally low levels of occiptial GABA have also been reported in subjects with premenstrual dyshoric disorder, a syndrome characterized by mood and behavioral alterations.155

Neuroimaging studies should attempt to longitudinally investigate GABAA receptor density and GABA levels in larger sample of first-episode drug-naive mood disorder patients and in high-risk patients for mood disorders. Important areas of focus may be the occipital cortex and other brain regions thought to be involved in the pathophysiology of mood disorders, such as prefrontal and medial temporal lobes (eg hippocampus, amygdala).156,157

Neuroendocrine studies

GABA modulates GH release at the hypothalamic level through a circuit involving GH releasing hormone and somatostatin.158,159 Baclofen, a GABAB receptor agonist, stimulates GH secretion in healthy individuals,160,161,162 and is considered to be an in vivo index of human hypothalamic GABAB receptor function. The GH response to baclofen has been found to be significantly lower in depressed patients163,164 and significantly higher in manic patients than healthy subjects.161 However, the findings suggesting abnormal regulation of GABAB receptors in mood disorder patients through the GH response are controversial, as other studies reported negative findings in depressed patients.162,165,166

Molecular biology and genetic studies

It has been reported that chronic administration of antidepressants (ie phenelzine and imipramine), benzodiazepines (ie alprazolam, lorazepam, and diazepam), and mood stabilizers (ie lamotrigine) may differentially modulate the gene expression of GABA receptor subunits in rat brain.167,168,169,170,171,172 These studies showed that the modulation of GABA receptor subunits, precisely GABAA, may vary in different brain regions, suggesting a regional heterogeneity that may be implicated in the mechanisms of action of antidepressants and mood stabilizers in mood disorder patients. In particular, phenelzine and imipramine have been reported to increase β2 and γ2 levels, but the former decreased α1 subunit expression, and the latter increased α1 expression in rat brainstem.171 Also, valproate, carbamazepine, and lithium173,174,175 upregulated GABAB receptors, but not GABAA receptors, in rat hippocampus and frontal cortex, whereas lamotrigine increased GABAA receptor β3 subunit expression in rat hippocampus.172 Therefore, antidepressants and mood stabilizers may have distinct effects in GABA receptor gene expression, which may be relevant for their mechanism of action in the treatment of mood disorder patients.

Heredity seems to play a major etiological role in the pathogenesis of affective disorder, as initially supported by findings from family, twin, and adoption studies.176 Several genetic investigations have tried to explore the association between specific GABA receptor genes and mood disorders. GABAA receptor α5 subunit (GABRA5) gene distribution has been found to be significantly different in unipolar177 and bipolar patients178 compared to healthy controls. Findings from a recent controlled multicenter study showed a significant association between GABAA receptor α1 subunit (GABRA1), but not GABRA5, and unipolar patients179 and between GABAA receptor α3 subunit (GABRA3), but not GABRA1 and GABRA5, and bipolar patients,180 suggesting that different GABAA receptor subunits may confer susceptibility to unipolar and bipolar disorders. A linkage study examining two large families segregating bipolar disorder could not exclude linkage of GABRA5 and GABAA receptor β1 subunit (GABRB1) loci in one of the families, although negative results were reported in the other study.181 However, several studies reported negative findings for GABAA receptor subunits in bipolar (GABRA1,2,3,4,5,6, GABRB1,3, GABRG2)177,181,182,183,184,185,186,187,188,189 and unipolar disorders (GABRA3, GABRA5).178,179

Although some support for association between GABRA1, GABRA3, and GABRA5 and mood disorders have been reported, the findings from the genetic studies taken together remain conflicting and preliminary. Thus, to this date, the linkage between mood disorder and GABA gene transmission continues to be largely inconclusive. Nonetheless, GABA receptor genes still remain primer targets for search in mood disorder, as supported by GABAergic abnormalities reported by other several lines of evidence, and need to be further investigated in future studies involving larger patient samples.

GABAergic modulation in the treatment of mood disorders

Mood stabilizers (Table 2)

Preclinical studies of GABA metabolism and GABA receptors

Administration of mood stabilizers, such as valproate, carbamazepine, lithium, and lamotrigine, has been reported to increase GABA turnover in mouse and rat brain.190,191,192,193 It has been shown that chronic lithium administration may increase GAD activity in rat frontal cortex and midbrain,194,195 GABA levels in rat hypothalamus, amygdala, and striatum,195,196 GABA release in primary culture of striatal neurons,197 and may decrease GABA receptor binding sites in rat hypothalamus and striatum.198 Both lithium and valproate have been reported to increase rat CSF GABA levels.199 Regarding valproate, animal studies reported that it enhances GABA levels,200,201,202,203 GABA synaptic release,203 GAD activity,204 neuronal GABA responsiveness,205 and inhibits GABA-T in several brain regions.206,207 Upregulation of GABAB receptors, but not GABAA receptors, has been found in rat hippocampus and frontal cortex after chronic administration of lithium, valproate, carbamazepine, fengabide, and progabide.173,174,175 However, an increase in gene expression of GABAA receptor β3 subunit in rat hippocampus after chronic administration of lamotrigine has been recently described.172

Table 2 Effects of mood stabilizers and antidepressants on GABAergic neurotransmission

Clinical studies

(1) CSF and plasma studies. Berrettini et al 98 reported that lithium increased the CSF and plasma levels of GABA in euthymic bipolar patients, although they did not replicate these findings in a second larger study.102 Valproate has been shown to increase plasma GABA levels in human individuals,208,209,210 suggesting that it enhances brain GABA activity. Petty et al 131 reported that higher pretreatment GABA plasma levels predicted response to valproate in acute manic patients, and did not correlate with symptom severity. In contrast, carbamazepine did not have any effects on CSF GABA levels in bipolar patients.211 (2) Neuroimaging studies. A PET study showed that valproate reduces GABAA receptor binding in young patients with absence of epilepsy compared to subjects not treated with valproate in several brain areas such as frontal cortex, temporal cortex, and basal ganglia.212 We are not aware of any neuroimaging study that examined GABA receptors after treatment with mood stabilizers in mood disorder patients. In vivo MRS studies found an increase in human GABA levels after gabapentin,213 topiramate,214 and vigabatrin administration,215 which are new anticonvulsants suggested to be effective in particular cases of mood disorders.216 (3) Neuroendocrine challenge studies. Valproate attenuated the GH response to baclofen in healthy subjects, with a direct correlation between this response and valproate blood levels,217 suggesting that valproate may downregulate human GABAB receptor function. (4) Genetic studies. No association between lithium-responsiveness and GABAA subunit candidate genes (GABRA1, GABRA3, GABRA5, and GABRB3) has been reported in bipolar disorder patients.185,218

Antidepressants (Table 2)

Preclinical studies of GABA metabolism and GABA receptor

It has been shown that chronic administration of antidepressants, such as imipramine, desipramine, trimipramine, maprotiline, nomifensine, and citalopram, reduces the levels of GABAA receptors in rat brains, in regions such as the cortex, hyppocampus, and hypothalamus,48,219,220,221 but not in all studies.173,222,223,224,225 Additionally, several studies reported increased GABAB receptor binding sites in frontal cortex and hippocampus in rats, after chronic treatment with various antidepressant drugs (ie amitryptyline, imipramine, desipramine, maprotiline, viloxazine, fluoxetine, citalopram),173,222,226,227,228 although not in all studies.228,229,230,231 Moreover, imipramine and desipramine reversed the decrease in GABAB receptors involved in helplessness in frontal cortex in rats,82 and baclofen (GABAB receptor agonist), but not muscimol (GABAA receptor agonist), attenuated the antidepressant effects in helplessness in rats.80,81 Several studies reported that chronic administration of antidepressants may increase baclofen-induced responses in mouse's frontal cortex and hippocampus,48,226,232,233 but not in all studies.228,234,235,236 Also, it has been reported that acute and chronic administration of phenelzine, a monoamine oxidase inhibitor, in rats may increase GABA brain levels by inhibiting GABA-T or GAD,224,237,238,239,240 or by increasing the GABA transporter GAT-1,241 and that imipramine may enhance GABA release in thalamus in rats.242 Sertraline243 and reboxetine244 have also been shown to reduce GAD expression in rat brain (ie prefrontal cortex, nucleus accumbens, thalamus, and limbic structures). Hyperforin, a major component of hypericum extract, which has been reported to be effective as antidepressant,245 may inhibit GABA synaptosomal uptake in rat forebrain, elevating GABA levels.246 It is stimulating to note that Griffin and Mellon247 have reported that certain SSRIs directly alter the activity of neurosteroidogenic enzymes in the CNS. As the authors suggested, this effect may lead to increased production of neurosteroids in the brain, potentially modulating GABA-associated behaviors. During the last 10 years, much effort has been directed to determine the potential role of neurosteroids in mood disorders. Nowadays, the dominant idea emerging from preclinical and clinical studies is that neurosteroids could be involved in the pathophysiology of affective disorders as well as in the mechanism of action of selective serotonin reuptake inhibitors (SSRIs).66 For example, potential antidepressant effects of allopregnanolone administration have been shown in animal studies,248,249 probably resulting from the enhancement of GABAergic, noradrenergic, and serotonergic neurotransmissions.66 In turn, several antidepressants, especially SSRIs, have been found to normalize plasma and CSF levels of allopregnanolone in depressed patients.250,251,252

Clinical studies

(1) Plasma GABA levels. No alteration of GABA plasma levels has been found in depressed patients before and after antidepressant treatment.121,122,132 (2) Neuroendocrine challenge studies. Monteleone et al165,253 did not find any differences in GH response to baclofen between depressed (N=10) and healthy subjects (N=9), and no modification of this response in depressed patients after chronic administration of antidepressants (ie fluoxetine, amitriptyline, imipramine). These results would not support the idea that GABAB receptors are involved in the mechanism of action of such antidepressant drugs. However, these findings were limited by the small sample size. (3) Neuroimaging studies. A recent MRS study reported significant increased levels of GABA in occipital cortex of depressed unmedicated patients after 2 months of SSRI treatment (ie fluoxetine or citalopram), possibly suggesting a normalization of low pretreatment GABA concentrations.154


Benzodiazepines increase the GABA-stimulated choride efflux by binding the GABAA receptor subunit α.254,255 Diazepam has been reported to increase the brain peak GABA-evoked current by accelerating GABA association to its receptors,254 and to enhance CSF GABA levels in humans.256 Human plasma GABA levels have been shown to be reduced by diazepam and lorazepam administration.257 Functional studies reported that GABAA receptors may be involved in BDZ effects on cerebral metabolism and in BDZ tolerance in humans.258,259,260,261

Also, the reported efficacy of BDZs in treating acute mood disorder patients is consistent with the hypothesis of a GABAergic deficit in mood disorders. Clonazepam and lorazepam have indeed been suggested to be useful in manic patients.262 Clonazepam, alprazolam, and adizolam have also been reported to be efficacious in treating depression in bipolar and unipolar patients.263,264,265,266 Alprazolam should generally be avoided in the treatment of manic states in bipolar patients, as cases of alprazolam-induced mania have been reported.262


Clozapine and olanzapine, but neither haloperidol nor chloropromazine, decreased the density of GABAA receptors in temporal cortex and hippocampus in rats,267 and clozapine sharply decreased GABA levels in rat prefrontal cortex and globus pallidus.268,269 Therefore, it is conceivable that some of the effects of these atypical antipsychotics in mood disorder patients would be modulated by effects in GABAergic systems.270

Electroconvulsive therapy

ECT is a tool with a wide application in psychiatry.271 Particularly, it exerts antidepressant and antimanic effectiveness in resistant mood disorder patients. ECT acutely decreased GABA release or GABA synthesis in rat brain272,273 and plasma GABA levels in depressed patients.130 On the contrary, with repeated ECT, increases in GABA release, GABA concentration, and GABAB biding sites have been reported in rat brain.173,274,275 These findings suggest that modulation of GABAergic pathways is involved in ECT mechanisms of action.

The findings from preclinical and clinical studies suggest that mood stabilizers, antidepressants, and ECT involve modulation of GABAergic neurotransmission and GABAB bindings sites. The increase in GABAB receptor levels in rat brain, preferentially in frontal cortex and hippocampus, seems specific to antidepressants and mood stabilizers, in particular valproate, whereas neuroleptics, anxiolytics, and other antiepileptics have not shown such effects.173,267 Thus, the hypothesis of a GABA deficit in mood disorder is also suggested by the mechanism of available treatments for these disorders. Moreover, preliminary clinical findings suggested that GABAergic agents, such as progabide and fengabide, may be effective in the treatment of depressed mood disorder patients.276,277,278,279,280,281 The potential involvement of GABAergic transmission in the mechanisms of action of mood stabilizers and antidepressants still remains elusive, especially regarding GABA receptors. Several studies have reported that GABAA receptors are decreased after treatment with valproate,212 antidepressants,45,220 and even with new antipsychotics, such as olanzapine and clozapine,267 which are also of utility in the treatment of mood disorders. As reviewed in the first section of the paper, GABAA and GABAB receptors interact with several second messengers, have different synaptical position, and elicit various neuronal effects. For example, as suggested by Suzdak and Gianutsos,226 the chronic administration of antidepressants may increase GABAB receptor functions by increasing cAMP production. Preclinical studies should focus on the GABAA and GABAB receptor intracellular mechanism of activation and on their effects in various brain regions. Also, to our best knowledge, no study thus far has evaluated in vivo the levels of GABA brain receptors in naïve and treated mood disorder patients. Thus, neuroimaging studies evaluating the action of mood stabilizers and antidepressants on GABA receptors in mood disorder subjects will be helpful to further investigate the mechanisms of action of available treatments for mood disorders.


As reviewed above, animal and clinical studies suggested, although with conflicting findings, that a deficit in GABAergic activity may be crucial in the pathophysiology of mood disorders. Also, GABAergic transmission appears to be involved in the mechanism of action of antidepressants, mood stabilizers, and ECT, in addition to benzodiazepines and new antipsychotics (ie olanzapine and clozapine), which are tools used in the treatment of mood disorders.216,270 However, these drugs involve several neurotransmitter systems, such as serotonergic, monoaminergic, and GABAergic systems.33,44,54 Petty argued87,282 that GABAergic transmission may mediate noradrenergic function in a unified concept of antidepressant mechanism of action that is complement to the noradrenergic theory of mood disorder. Based on this hypothesis and on the modulation of monoaminergic and serotonergic systems by GABAergic pathways, it is possible to speculate that low basal GABA level may lead to reduced level of monoaminergic and serotonergic transmissions. Therefore, the hypothesis of GABAergic neurotransmission deficit in mood disorders would be complementary to the well-established alterations in monoaminergic and serotonergic systems, suggesting that the balance between multiple neural transmissions may be altered in these disorders.

Nonetheless, the hypothesis of a GABAergic dysfunction in mood disorders has some limitations. First, reported abnormalities may not be specific to mood disorders, as GABAergic alterations have also been suggested in the pathophysiology of schizophrenia283 and panic disorder.284,285 Also, evidence that GABAergic modulation results in antidepressant effects is still missing, although robust evidence of efficacy of GABAergic medications has been shown in bipolar disorder patients.78,216,281 Moreover, extrapolation from biochemical observations in preclinical studies to clinical expression of mood disorders is difficult, since animal models only partly resemble human phenotypic manifestation of the disease. Last, no animal model replicating manic clinical features has yet been developed.

In conclusion, several different lines of evidence suggest that low GABAergic function may play a key role in the pathophysiology of mood disorders, which probably relates to dysfunctions in multiple neurotransmitter systems. It is unclear at this point which abnormality would be primary or secondary, but future research into the role of GABAergic pathways in pathophysiology of mood disorders should attempt to clarify it. Decreased GABA activity, if present, would probably be a feature of a subset of mood disorder patients, possibly representing a genetic susceptibility to develop unipolar or bipolar disorder. Future studies should better explore the relationship between monoaminergic, serotonergic, and GABAergic system and should further clarify the potential mechanisms implicated in the transmission of a GABA deficit in mood disorders.


  1. 1

    Zachmann M, Tocci P, Nyhan WL . The occurrence of gamma-aminobutyric acid in human tissues other than brain. J Biol Chem 1966; 241: 1355–1358.

    CAS  PubMed  Google Scholar 

  2. 2

    Otsuka M, Iversen LL, Hall ZW, Kravitz EA . Release of gamma-aminobutyric acid from inhibitory nerves of lobster. Proc Natl Acad Sci USA 1966; 56: 1110–1115.

    CAS  PubMed  Google Scholar 

  3. 3

    Meldrum B . Pharmacology of GABA. Clin Neuropharmacol 1982; 5: 293–316.

    CAS  PubMed  Google Scholar 

  4. 4

    Guidotti A, Corda MG, Wise BC, Vaccarino F, Costa E . GABAergic synapses. Supramolecular organization and biochemical regulation. Neuropharmacology 1983; 22: 1471–1479.

    CAS  PubMed  Google Scholar 

  5. 5

    Emrich HM, von Zerssen D, Kissling W, Moller HJ, Windorfer A . Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Archiv Psychiatrie Nervenkrankheiten 1980; 229: 1–16.

    CAS  Google Scholar 

  6. 6

    Massat I, Sourey D, Papadimitriou GN, Mendlewicz J . The GABAergic hypothesis of mood disorders. In: Soares JC, Gershon S (eds). Bipolar Disorders, Basic Mechanisms and Therapeutic Implication. Marcel Dekker: New York, 2000, pp. 143–165.

    Google Scholar 

  7. 7

    Peng L, Hertz L, Huang R, Sonnewald U, Petersen SB, Westergaard N et al. Utilization of glutamine and of TCA cycle constituents as precursors for transmitter glutamate and GABA. Dev Neurosci 1993; 15: 367–377.

    CAS  PubMed  Google Scholar 

  8. 8

    Schousboe A, Westergaard N, Sonnewald U, Petersen SB, Huang R, Peng L et al. Glutamate and glutamine metabolism and compartmentation in astrocytes. Dev Neurosci 1993; 15: 359–366.

    CAS  PubMed  Google Scholar 

  9. 9

    Durkin MM, Smith KE, Borden LA, Weinshank RL, Branchek TA, Gustafson EL . Localization of messenger RNAs encoding three GABA transporters in rat brain: an in situ hybridization study. Brain Res Mol Brain Res 1995; 33: 7–21.

    CAS  PubMed  Google Scholar 

  10. 10

    Borden LA . GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int 1996; 29: 335–356.

    CAS  PubMed  Google Scholar 

  11. 11

    Cherubini E, Conti F . Generating diversity at GABAergic synapses. Trends Neurosci 2001; 24: 155–162.

    CAS  PubMed  Google Scholar 

  12. 12

    Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ . Two genes encode distinct glutamate decarboxylases. Neuron 1991; 7: 91–100.

    CAS  PubMed  Google Scholar 

  13. 13

    Eder M, Rammes G, Zieglgansberger W, Dodt H-U . GABAA and GABAB receptors on neocortical neurons are differentialy distributed. Eur J Neurosci 2001; 13: 1065–1069.

    CAS  PubMed  Google Scholar 

  14. 14

    Costa E, Auta J, Grayson DR, Matsumoto K, Pappas GD, Zhang X et al. GABAA receptors and benzodiapines: a role for dendritic resident subunit mRNAs. Neuropharmacology 2002; 43: 925–937.

    CAS  PubMed  Google Scholar 

  15. 15

    Bormann J . Electrophysiology of GABAA and GABAB receptor subtypes. Trends Neurosci 1988; 11: 112–116.

    CAS  PubMed  Google Scholar 

  16. 16

    Macdonald RL, Twyman RE, Ryan-Jastrow T, Angelotti TP . Regulation of GABAA receptor channels by anticonvulsant and convulsant drugs and by phosphorylation. Epilepsy Res Suppl 1992; 9: 265–277.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Haefely W, Kulcsar A, Mohler H . Possible involvement of GABA in the central actions of benzodiazepines. Psychopharmacol Bull 1975; 11: 58–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Nicoll RA, Eccles JC, Oshima T, Rubia F . Prolongation of hippocampal inhibitory postsynaptic potentials by barbiturates. Nature 1975; 258: 625–627.

    CAS  PubMed  Google Scholar 

  19. 19

    Narahashi T, Arakawa O, Brunner EA, Nakahiro M, Nishio M, Ogata N et al. Modulation of GABA receptor-channel complex by alcohols and general anesthetics. Adv Biochem Psychopharmacol 1992; 47: 325–334.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Mhatre M, Ticku MK . Chronic ethanol treatment upregulates the GABA receptor beta subunit expression. Brain Res Mol Brain Res 1994; 23: 246–252.

    CAS  PubMed  Google Scholar 

  21. 21

    Curtis DR, Duggan AW, Felix D, Johnston GA . Bicuculline and central GABA receptors. Nature 1970; 228: 676–677.

    CAS  PubMed  Google Scholar 

  22. 22

    Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M et al. International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function. Pharmacol Rev 2002; 54: 247–264.

    CAS  PubMed  Google Scholar 

  23. 23

    Karbon EW, Duman RS, Enna SJ . GABAB receptors and norepinephrine-stimulated cAMP production in rat brain cortex. Brain Res 1984; 306: 327–332.

    CAS  PubMed  Google Scholar 

  24. 24

    Pycock CJ, Horton RW . Dopamine-dependent hyperactivity in the rat following manipulation of GABA mechanisms in the region of the nucleus accumbens. J Neural Transm 1979; 45: 17–33.

    CAS  PubMed  Google Scholar 

  25. 25

    Jones MW, Kilpatrick IC, Phillipson OT . Dopamine function in the prefrontal cortex of the rat is sensitive to a reduction of tonic GABA-mediated inhibition in the thalamic mediodorsal nucleus. Exp Brain Res 1988; 69: 623–634.

    CAS  PubMed  Google Scholar 

  26. 26

    Reid M, Herrera-Marschitz M, Hokfelt T, Terenius L, Ungerstedt U . Differential modulation of striatal dopamine release by intranigral injection of gamma-aminobutyric acid (GABA), dynorphin A and substance P. Eur J Pharmacol 1988; 147: 411–420.

    CAS  PubMed  Google Scholar 

  27. 27

    Benes FM, Vincent SL, Molloy R . Dopamine-immunoreactive axon varicosities form nonrandom contacts with GABA-immunoreactive neurons of rat medial prefrontal cortex. Synapse 1993; 15: 285–295.

    CAS  PubMed  Google Scholar 

  28. 28

    Dewey SL, Smith GS, Logan J, Brodie JD, Yu DW, Ferrieri RA et al. GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci 1992; 12: 3773–3780.

    CAS  PubMed  Google Scholar 

  29. 29

    Schiffer WK, Gerasimov MR, Bermel RA, Brodie JD, Dewey SL . Stereoselective inhibition of dopaminergic activity by gamma vinyl-GABA following a nicotine or cocaine challenge: a PET/microdialysis study. Life Sci 2000; 66: L169–L173.

    Google Scholar 

  30. 30

    Ring HA, Trimble MR, Costa DC, George MS, Verhoeff P, Ell PJ . Effect of vigabatrin on striatal dopamine receptors: evidence in humans for interactions of GABA and dopamine systems. J Neurol Neurosurg Psychiatry 1992; 55: 758–761.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Garbutt JC, van Kammen DP . The interaction between GABA and dopamine: implications for schizophrenia. Schizophr Bull 1983; 9: 336–353.

    CAS  PubMed  Google Scholar 

  32. 32

    Evangelista S, Borsini F, Meli A . Evidence that muscimol acts in the forced swimming test by activating the rat dopaminergic system. Life Sci 1987; 41: 2679–2684.

    CAS  PubMed  Google Scholar 

  33. 33

    Bonanno G, Raiteri M . Coexistence of carriers for dopamine and GABA uptake on a same nerve terminal in the rat brain. Br J Pharmacol 1987; 91: 237–243.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Retaux S, Besson MJ, Penit-Soria J . Opposing effects of dopamine D2 receptor stimulation on the spontaneous and the electrically evoked release of [3H]GABA on rat prefrontal cortex slices. Neuroscience 1991; 42: 61–71.

    CAS  PubMed  Google Scholar 

  35. 35

    Floran B, Floran L, Sierra A, Aceves J . D2 receptor-mediated inhibition of GABA release by endogenous dopamine in the rat globus pallidus. Neurosci Lett 1997; 237: 1–4.

    CAS  PubMed  Google Scholar 

  36. 36

    Grobin AC, Deutch AY . Dopaminergic regulation of extracellular gamma-aminobutyric acid levels in the prefrontal cortex of the rat. J Pharmacol Exp Ther 1998; 285: 350–357.

    CAS  PubMed  Google Scholar 

  37. 37

    Harsing Jr LG, Zigmond MJ . Influence of dopamine on GABA release in striatum: evidence for D1−D2 interactions and non-synaptic influences. Neuroscience 1997; 77: 419–429.

    CAS  PubMed  Google Scholar 

  38. 38

    Seamans JK, Gorelova N, Durstewitz D, Yang CR . Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 2001; 21: 3628–3638.

    CAS  PubMed  Google Scholar 

  39. 39

    Wang X, Zhong P, Yan Z . Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. J Neurosci 2002; 22: 9185–9193.

    CAS  PubMed  Google Scholar 

  40. 40

    Cobb WS, Abercrombie ED . Distinct roles for nigral GABA and glutamate receptors in the regulation of dendritic dopamine release under normal conditions and in response to systemic haloperidol. J Neurosci 2002; 22: 1407–1413.

    CAS  PubMed  Google Scholar 

  41. 41

    Biswas B, Carlsson A . The effect of intracerebroventricularly administered GABA on brain monoamine metabolism. Naunyn Schmiedebergs Arch Pharmacol 1977; 299: 41–46.

    CAS  PubMed  Google Scholar 

  42. 42

    Biswas B, Carlsson A . The effect of intraperitoneally administered GABA on brain monoamine metabolism. Naunyn Schmiedebergs Arch Pharmacol 1977; 299: 47–51.

    CAS  PubMed  Google Scholar 

  43. 43

    Scatton B, Zivkovic B, Dedek J, Lloyd KG, Constantinidis J, Tissot R et al. Gamma-Aminobutyric acid (GABA) receptor stimulation. III. Effect of progabide (SL 76002) on norepinephrine, dopamine and 5-hydroxytryptamine turnover in rat brain areas. J Pharmacol Exp Ther 1982; 220: 678–688.

    CAS  PubMed  Google Scholar 

  44. 44

    Scatton B, Lloyd KG, Zivkovic B, Dennis T, Claustre Y, Dedek J et al. Fengabine, a novel antidepressant GABAergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABAergic transmission in the rat. J Pharmacol Exp Ther 1987; 241: 251–257.

    CAS  PubMed  Google Scholar 

  45. 45

    Suzdak PD, Gianutsos G . Differential coupling of GABA-A and GABA-B receptors to the noradrenergic system. J Neural Transm 1985; 62: 77–89.

    CAS  PubMed  Google Scholar 

  46. 46

    Bonanno G, Raiteri M . Carriers for GABA and noradrenaline uptake coexist on the same nerve terminal in rat hippocampus. Eur J Pharmacol 1987; 136: 303–310.

    CAS  PubMed  Google Scholar 

  47. 47

    Bonanno G, Raiteri M . Release-regulating GABAA receptors are present on noradrenergic nerve terminals in selective areas of the rat brain. Synapse 1987; 1: 254–257.

    CAS  PubMed  Google Scholar 

  48. 48

    Suzdak PD, Gianutsos G . Parallel changes in the sensitivity of gamma-aminobutyric acid and noradrenergic receptors following chronic administration of antidepressant and GABAergic drugs. A possible role in affective disorders. Neuropharmacology 1985; 24: 217–222.

    CAS  PubMed  Google Scholar 

  49. 49

    Ferraro L, Tanganelli S, Calo G, Antonelli T, Fabrizi A, Acciarri N et al. Noradrenergic modulation of gamma-aminobutyric acid outflow from the human cerebral cortex. Brain Res 1993; 629: 103–108.

    CAS  PubMed  Google Scholar 

  50. 50

    Mitoma H, Konishi S . Monoaminergic long-term facilitation of GABA-mediated inhibitory transmission at cerebellar synapses. Neuroscience 1999; 88: 871–883.

    CAS  PubMed  Google Scholar 

  51. 51

    Nishikawa T, Scatton B . Evidence for a GABAergic inhibitory influence on serotonergic neurons originating from the dorsal raphe. Brain Res 1983; 279: 325–329.

    CAS  PubMed  Google Scholar 

  52. 52

    Nishikawa T, Tanaka M, Tsuda A, Kohno Y, Nagasaki N . Serotonergic−catecholaminergic interactions and foot shock-induced jumping behavior in rats. Eur J Pharmacol 1983; 94: 53–58.

    CAS  PubMed  Google Scholar 

  53. 53

    Nishikawa T, Scatton B . Inhibitory influence of GABA on central serotonergic transmission. Raphe nuclei as the neuroanatomical site of the GABAergic inhibition of cerebral serotonergic neurons. Brain Res 1985; 331: 91–103.

    CAS  PubMed  Google Scholar 

  54. 54

    Francois-Bellan AM, Hery M, Faldon M, Hery F . Evidence for GABA on serotonin metabolism in the rat suprachiasmatic area. Neurochem Int 1988; 134: 455–462.

    Google Scholar 

  55. 55

    Bagdy E, Kiraly I, Harsing LG . Reciprocal innervation between serotonergic and GABAergic neurons in raphe nuclei of the rat. Neurochem Res 2000; 25: 1465–1473.

    CAS  PubMed  Google Scholar 

  56. 56

    Shen RY, Andrade R . 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J Pharmacol Exp Ther 1998; 285: 805–812.

    CAS  PubMed  Google Scholar 

  57. 57

    Abi-Saab WM, Bubser M, Roth RH, Deutch AY . 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology 1999; 20: 92–96.

    CAS  PubMed  Google Scholar 

  58. 58

    Liu R, Jolas T, Aghajanian G . Serotonin 5-HT(2) receptors activate local GABA inhibitory inputs to serotonergic neurons of the dorsal raphe nucleus. Brain Res 2000; 873: 34–45.

    CAS  PubMed  Google Scholar 

  59. 59

    Green AR, Johnson P, Mountford JA, Nimgaonkar VL . Some anticonvulsant drugs alter monoamine-mediated behaviour in mice in ways similar to electroconvulsive shock; implications for antidepressant therapy. Br J Pharmacol 1985; 84: 337–346.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Metz A, Goodwin GM, Green AR . The administration of baclofen to mice increases 5-HT2-mediated head-twitch behaviour and 5-HT2 receptor number in frontal cortex. Neuropharmacology 1985; 24: 357–360.

    CAS  PubMed  Google Scholar 

  61. 61

    Gray JA, Metz A, Goodwin GM, Green AR . The effects of the GABA-mimetic drugs, progabide and baclofen, on the biochemistry and function of 5-hydroxytryptamine and noradrenaline. Neuropharmacology 1986; 25: 711–716.

    CAS  PubMed  Google Scholar 

  62. 62

    Sibille E, Pavlides C, Benke D, Toth M . Genetic inactivation of the Serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J Neurosci 2000; 20: 2758–2765.

    CAS  PubMed  Google Scholar 

  63. 63

    Maggi A, Perez J . Role of female gonadal hormones in the CNS: clinical and experimental aspects. Life Sci 1985; 37: 893–906.

    CAS  PubMed  Google Scholar 

  64. 64

    Perez J, Zucchi A, Maggi A . Sexual dimorphism in the response of the GABAergic system to estrogen administration. J Neurochem 1986; 47: 1798–1803.

    CAS  PubMed  Google Scholar 

  65. 65

    McEwen BS . Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci 1991; 12: 141–147.

    CAS  PubMed  Google Scholar 

  66. 66

    van Broekhoven F, Verkes RJ . Neurosteroids in depression: a review. Psychopharmacology 2003; 165: 97–110.

    CAS  PubMed  Google Scholar 

  67. 67

    Do-Rego JL, Mensah-Nyagan GA, Beaujean D, Vaudry D, Sieghart W, Luu-The V et al. Gamma-Aminobutyric acid, acting through gamma-aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus. Proc Natl Acad Sci USA 2000; 97: 13925–13930.

    CAS  PubMed  Google Scholar 

  68. 68

    Haage D, Druzin M, Johansson S . Allopregnanolone modulates spontaneous GABA release via presynaptic Cl permeability in rat preoptic nerve terminals. Brain Res 2002; 958: 405–413.

    CAS  PubMed  Google Scholar 

  69. 69

    McIntyre KL, Porter DM, Henderson LP . Anabolic androgenic steroids induce age-, sex-, and dose-dependent changes in GABAA receptor subunit mRNAs in the mouse forebrain. Neuropharmacology 2002; 43: 634–645.

    CAS  PubMed  Google Scholar 

  70. 70

    Porsolt RD, Anton G, Blavet N, Jalfre M . Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978; 47: 379–391.

    CAS  Google Scholar 

  71. 71

    Mancinelli A, D'Aranno V, Borsini F, Meli A . Lack of relationship between effect of desipramine on forced swimming test and brain levels of desipramine or its demethylated metabolite in rats. Psychopharmacology 1987; 92: 441–443.

    CAS  PubMed  Google Scholar 

  72. 72

    Borsini F, Mancinelli A, D'Aranno V, Evangelista S, Meli A . On the role of endogenous GABA in the forced swimming test in rats. Pharmacol Biochem Behav 1987; 29: 275–279.

    Google Scholar 

  73. 73

    Poncelet M, Martin P, Danti S, Simon P, Soubrie P . Noradrenergic rather than GABAergic processes as the common mediation of the antidepressant profile of GABA agonists and imipraminelike drugs in animals. Pharmacol Biochem Behav 1987; 28: 321–326.

    CAS  PubMed  Google Scholar 

  74. 74

    Seligman ME, Maier SF . Failure to escape traumatic shock. J Exp Psychol 1967; 74: 1–9.

    CAS  PubMed  Google Scholar 

  75. 75

    Sherman AD, Petty F . Neurochemical basis of the action of antidepressants on learned helplessness. Behav Neural Biol 1980; 30: 119–134.

    CAS  PubMed  Google Scholar 

  76. 76

    Petty F, Sherman AD . GABAergic modulation of learned helplessness. Pharmacol Biochem Behav 1981; 15: 567–570.

    CAS  Google Scholar 

  77. 77

    Sherman AD, Petty F . Additivity of neurochemical changes in learned helplessness and imipramine. Behav Neural Biol 1982; 35: 344–353.

    CAS  PubMed  Google Scholar 

  78. 78

    Lloyd KG, Morselli PL, Depoortere H, Fournier V, Zivkovic B, Scatton B et al. The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials. Pharmacol Biochem Behav 1983; 18: 957–966.

    CAS  PubMed  Google Scholar 

  79. 79

    Drugan RC, Morrow AL, Weizman R, Weizman A, Deutsch SI, Crawley JN et al. Stress-induced behavioral depression in the rat is associated with a decrease in GABA receptor-mediated chloride ion flux and brain benzodiazepine receptor occupancy. Brain Res 1989; 487: 45–51.

    CAS  PubMed  Google Scholar 

  80. 80

    Nakagawa Y, Ishima T, Ishibashi Y, Tsuji M, Takashima T . Involvement of GABAB receptor systems in experimental depression: baclofen but not bicuculline exacerbates helplessness in rats. Brain Res 1996; 741: 240–245.

    PubMed  Google Scholar 

  81. 81

    Nakagawa Y, Ishima T, Ishibashi Y, Tsuji M, Takashima T . Involvement of GABAB receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats. Brain Res 1996; 728: 225–230.

    CAS  PubMed  Google Scholar 

  82. 82

    Martin P, Pichat P, Massol J, Soubrie P, Lloyd KG, Puech AJ . Decreased GABA B receptors in helpless rats: reversal by tricyclic antidepressants. Neuropsychobiology 1989; 22: 220–224.

    CAS  PubMed  Google Scholar 

  83. 83

    Plaznik A, Tamborska E, Hauptmann M, Bidzinski A, Kostowski W . Brain neurotransmitter systems mediating behavioral deficits produced by inescapable shock treatment in rats. Brain Res 1988; 447: 122–132.

    CAS  PubMed  Google Scholar 

  84. 84

    Corda MG, Blaker WD, Mendelson WB, Guidotti A, Costa E . beta-Carbolines enhance shock-induced suppression of drinking in rats. Proc Natl Acad Sci USA 1983; 80: 2072–2076.

    CAS  PubMed  Google Scholar 

  85. 85

    Drugan RC, Maier SF, Skolnick P, Paul SM, Crawley JN . An anxiogenic benzodiazepine receptor ligand induces learned helplessness. Eur J Pharmacol 1985; 113: 453–457.

    CAS  PubMed  Google Scholar 

  86. 86

    Guidotti A, Ferrero P, Costa E . On the brain endocoid for benzodiazepine recognition sites. Prog Clin Biol Res 1985; 192: 477–484.

    CAS  PubMed  Google Scholar 

  87. 87

    Kelly JP, Wrynn AS, Leonard BE . The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther 1997; 74: 299–316.

    CAS  PubMed  Google Scholar 

  88. 88

    Jancsar SM, Leonard BE . Changes in neurotransmitter metabolism following olfactory bulbectomy in the rat. Prog Neuropsychopharmacol Biol Psychiatry 1984; 8: 263–269.

    CAS  PubMed  Google Scholar 

  89. 89

    Lloyd KG, Pichat P . Decrease in GABAB binding to the frontal cortex of olfactory bulbectomized rats. Br J Pharmacol 1986; 87: 36.

    Google Scholar 

  90. 90

    Dennis T, Beauchemin V, Lavoie N . Differential effects of olfactory bulbectomy on GABAA and GABAB receptors in the rat brain. Pharmacol Biochem Behav 1993; 46: 77–82.

    CAS  PubMed  Google Scholar 

  91. 91

    Joly D, Lloyd KG, Pichat P, Sanger DJ . Correlation between the behavioral effect of desipramine and GABAB receptor regulation in the olfactory bulbectomized rat. Br J Pharmacol 1987; 90: 125.

    Google Scholar 

  92. 92

    Leonard BE, Tuite M . Anatomical, physiological, and behavioral aspects of olfactory bulbectomy in the rat. Int Rev Neurobiol 1981; 22: 251–286.

    CAS  PubMed  Google Scholar 

  93. 93

    Lloyd KG, Zivkovic B, Sanger D, Depoortere H, Bartholini G . Fengabine, a novel antidepressant GABAergic agent. I. Activity in models for antidepressant drugs and psychopharmacological profile. J Pharmacol Exp Ther 1987; 241: 245–250.

    CAS  PubMed  Google Scholar 

  94. 94

    Grove J, Schechter PJ, Hanke NF, de Smet Y, Agid Y, Tell G et al. Concentration gradients of free and total gamma-aminobutyric acid and homocarnosine in human CSF: comparison of suboccipital and lumbar sampling. J Neurochem 1982; 39: 1618–1622.

    CAS  PubMed  Google Scholar 

  95. 95

    Loscher W . Relationship between GABA concentrations in cerebrospinal fluid and seizure excitability. J Neurochem 1982; 38: 293–295.

    CAS  PubMed  Google Scholar 

  96. 96

    Gold BI, Bowers Jr MB, Roth RH, Sweeney DW . GABA levels in CSF of patients with psychiatric disorders. Am J Psychiatry 1980; 137: 362–364.

    CAS  PubMed  Google Scholar 

  97. 97

    Kasa K, Otsuki S, Yamamoto M, Sato M, Kuroda H, Ogawa N . Cerebrospinal fluid gamma-aminobutyric acid and homovanillic acid in depressive disorders. Biol Psychiatry 1982; 17: 877–883.

    CAS  PubMed  Google Scholar 

  98. 98

    Berrettini WH, Nurnberger Jr JI, Hare TA, Simmons-Alling S, Gershon ES, Post RM . reduced plasma and CSF gamma-aminobutyric acid in affective illness: effect of lithium carbonate. Biol Psychiatry 1983; 18: 185–194.

    CAS  PubMed  Google Scholar 

  99. 99

    Gerner RH, Hare TA . CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am J Psychiatry 1981; 138: 1098–1101.

    CAS  PubMed  Google Scholar 

  100. 100

    Gerner RH, Fairbanks L, Anderson GM, Young JG, Scheinin M, Linnoila M et al. CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls. Am J Psychiatry 1984; 141: 1533–1540.

    CAS  PubMed  Google Scholar 

  101. 101

    Post RM, Ballenger JC, Hare TA, Goodwin FK, Lake CR, Jimerson DC et al. Cerebrospinal fluid GABA in normals and patients with affective disorders. Brain Res Bull 1980; 5 (Suppl 2): 755–759.

    Google Scholar 

  102. 102

    Berrettini WH, Nurnberger Jr JI, Hare TA, Simmons-Alling S, Gershon ES . CSF GABA in euthymic manic-depressive patients and controls. Biol Psychiatry 1986; 21: 844–846.

    CAS  PubMed  Google Scholar 

  103. 103

    Joffe R, Post R, Rubinow D, Berrettini W, Hare T, Ballenger J et al. Cerebrospinal fluid GABA in manic-depressive illness. In: Bartholini G, Lloyd K, Morselli P (eds). GABA and Mood Disorders: Experimental and Clinical Research. Raven Press: New York, 1986.

    Google Scholar 

  104. 104

    Petty F, Kramer G, Feldman M . Is plasma GABA of peripheral origin? Biol Psychiatry 1987; 22: 725–732.

    CAS  PubMed  Google Scholar 

  105. 105

    Petty F . Plasma concentrations of gamma-aminobutyric acid (GABA) and mood disorders: a blood test for manic depressive disease? Clin Chem 1994; 40: 296–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Ferkany JW, Smith LA, Seifert WE, Caprioli RM, Enna SJ . Measurement of gamma-aminobutyric acid (GABA) in blood. Life Sci 1978; 22: 2121–2128.

    CAS  PubMed  Google Scholar 

  107. 107

    Bohlen P, Huot S, Palfreyman MG . The relationship between GABA concentrations in brain and cerebrospinal fluid. Brain Res 1979; 167: 297–305.

    CAS  PubMed  Google Scholar 

  108. 108

    Ferkany JW, Butler IJ, Enna SJ . Effect of drugs on rat brain, cerebrospinal fluid and blood GABA content. J Neurochem 1979; 33: 29–33.

    CAS  PubMed  Google Scholar 

  109. 109

    Loscher W . GABA in plasma and cerebrospinal fluid of different species. Effects of gamma-acetylenic GABA, gamma-vinyl GABA and sodium valproate. J Neurochem 1979; 32: 1587–1591.

    CAS  PubMed  Google Scholar 

  110. 110

    Apud JA, Racagni G, Iuliano E, Cocchi D, Casanueva F, Muller EE . Role of central nervous system-derived or circulating gamma-aminobutyric acid on prolactin secretion in the rat. Endocrinology 1981; 108: 1505–1510.

    CAS  PubMed  Google Scholar 

  111. 111

    Loscher W, Frey HH . Transport of GABA at the blood−CSF interface. J Neurochem 1982; 38: 1072–1079.

    CAS  PubMed  Google Scholar 

  112. 112

    Uhlhaas S, Lange H, Wappenschmidt J, Olek K . Free and conjugated CSF and plasma GABA in Huntington's chorea. Acta Neurol Scand 1986; 74: 261–265.

    CAS  PubMed  Google Scholar 

  113. 113

    Loscher W, Rating D, Siemes H . GABA in cerebrospinal fluid of children with febrile convulsions. Epilepsia 1981; 22: 697–702.

    CAS  PubMed  Google Scholar 

  114. 114

    Schmidt D, Loscher W . Plasma and cerebrospinal fluid gamma-aminobutyric acid in neurological disorders. J Neurol Neurosurg Psychiatry 1982; 45: 931–935.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Berrettini WH, Nurnberger Jr JI, Hare T, Gershon ES, Post RM . Plasma and CSF GABA in affective illness. Br J Psychiatry 1982; 141: 483–487.

    CAS  PubMed  Google Scholar 

  116. 116

    Petty F, Schlesser MA . Plasma GABA in affective illness. A preliminary investigation. J Affect Disord 1981; 3: 339–343.

    CAS  PubMed  Google Scholar 

  117. 117

    Petty F, Sherman AD . Plasma GABA levels in psychiatric illness. J Affect Disord 1984; 6: 131–138.

    CAS  PubMed  Google Scholar 

  118. 118

    Petty F, Kramer GL, Dunnam D, Rush AJ . Plasma GABA in mood disorders. Psychopharmacol Bull 1990; 26: 157–161.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Petty F, Kramer GL, Gullion CM, Rush AJ . Low plasma gamma-aminobutyric acid levels in male patients with depression. Biol Psychiatry 1992; 32: 354–363.

    CAS  PubMed  Google Scholar 

  120. 120

    Petty F, Kramer GL, Fulton M, Moeller FG, Rush AJ . Low plasma GABA is a trait-like marker for bipolar illness. Neuropsychopharmacol 1993; 9: 125–132.

    CAS  Google Scholar 

  121. 121

    Petty F, Steinberg J, Kramer GL, Fulton M, Moeller FG . Desipramine does not alter plasma GABA in patients with major depression. J Affect Disord 1993; 29: 53–56.

    CAS  PubMed  Google Scholar 

  122. 122

    Petty F, Kramer GL, Fulton M, Davis L, Rush AJ . Stability of plasma GABA at four-year follow-up in patients with primary unipolar depression. Biol Psychiatry 1995; 37: 806–810.

    CAS  PubMed  Google Scholar 

  123. 123

    Prosser J, Hughes CW, Sheikha S, Kowatch RA, Kramer GL, Rosenbarger N et al. Plasma GABA in children and adolescents with mood, behavior, and comorbid mood and behavior disorders: a preliminary study. J Child Adolesc Psychopharmacol 1997; 7: 181–199.

    CAS  PubMed  Google Scholar 

  124. 124

    Petty F, Kramer G . Stability of plasma gamma-aminobutyric acid with time in healthy controls. Biol Psychiatry 1992; 31: 743–745.

    CAS  PubMed  Google Scholar 

  125. 125

    Schulz P, Lustenberger S, Degli Agosti R, Rivest RW . Plasma concentration of nine hormones and neurotransmitters during usual activities or constant bed rest for 34 H. Chronobiol Int 1994; 11: 367–380.

    CAS  PubMed  Google Scholar 

  126. 126

    Schulz P, Lloyd KG, Voltz C, Lustenberger S, Agosti RD . The plasma concentration of GABA shows no evidence of a circadian rhythm and is stable over weeks in normal males. Biol Rhythm Res 1994; 25: 291–300.

    CAS  Google Scholar 

  127. 127

    Berrettini WH, Umberkoman-Wiita B, Nurnberger Jr. JI, Vogel WH, Gershon ES, Post RM . Platelet GABA-transaminase in affective illness. Psychiatry Res 1982; 7: 255–260.

    CAS  PubMed  Google Scholar 

  128. 128

    Kaiya H, Namba M, Yoshida H, Nakamura S . Plasma glutamate decarboxylase activity in neuropsychiatry. Psychiatry Res 1982; 6: 335–343.

    CAS  PubMed  Google Scholar 

  129. 129

    Nurnberger Jr. JI, Berrettini WH, Simmons-Alling S, Guroff JJ, Gershon ES . Intravenous GABA administration is anxiogenic in man. Psychiatry Res 1986; 19: 113–117.

    PubMed  Google Scholar 

  130. 130

    Devanand DP, Shapira B, Petty F, Kramer G, Fitzsimons L, Lerer B et al. Effects of electroconvulsive therapy on plasma GABA. Convuls Ther 1995; 11: 3–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Petty F, Rush AJ, Davis JM, Calabrese JR, Kimmel SE, Kramer GL et al. Plasma GABA predicts acute response to divalproex in mania. Biol Psychiatry 1996; 39: 278–284.

    CAS  PubMed  Google Scholar 

  132. 132

    Rode A, Bidzinski A, Puzynski S . GABA levels in the plasma of patients with endogenous depression and during the treatment with thymoleptics. Psychiatr Pol 1991; 25: 4–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Petty F, Fulton M, Moeller FG, Kramer G, Wilson L, Fraser K et al. Plasma gamma-aminobutyric acid (GABA) is low in alcoholics. Psychopharmacol Bull 1993; 29: 277–281.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Halbreich U, Petty F, Yonkers K, Kramer GL, Rush AJ, Bibi KW . Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder. Am J Psychiatry 1996; 153: 718–720.

    CAS  PubMed  Google Scholar 

  135. 135

    Yonkers KA . The association between premenstrual dysphoric disorder and other mood disorders. J Clin Psychiatry 1997; 58 (Suppl 15): 19–25.

    PubMed  PubMed Central  Google Scholar 

  136. 136

    Roy A, DeJong J, Lamparski D, George T, Linnoila M . Depression among alcoholics. Relationship to clinical and cerebrospinal fluid variables. Arch Gen Psychiatry 1991; 48: 428–432.

    CAS  Google Scholar 

  137. 137

    Goddard AW, Narayan M, Woods SW, Germine M, Kramer GL, Davis LL et al. Plasma levels of gamma-aminobutyric acid and panic disorder. Psychiatry Res 1996; 63: 223–225.

    CAS  PubMed  Google Scholar 

  138. 138

    Gerner RH, Cohen DJ, Fairbanks L, Anderson GM, Young JG, Scheinin M et al. CSF neurochemistry of women with anorexia nervosa and normal women. Am J Psychiatry 1984; 141: 1441–1444.

    CAS  PubMed  Google Scholar 

  139. 139

    Bjork JM, Moeller FG, Kramer GL, Kram M, Suris A, Rush AJ et al. Plasma GABA levels correlate with aggressiveness in relatives of patients with unipolar depressive disorder. Psychiatry Res 2001; 101: 131–136.

    CAS  PubMed  Google Scholar 

  140. 140

    Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE . Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 1977; 34: 247–265.

    CAS  PubMed  Google Scholar 

  141. 141

    Cheetham SC, Crompton MR, Katona CLE, Horton RW . Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 1988; 443: 272–280.

    CAS  PubMed  Google Scholar 

  142. 142

    Cross JA, Cheetham SC, Crompton MR, Katona CL, Horton RW . Brain GABAB binding sites in depressed suicide victims. Psychiatry Res 1988; 26: 119–129.

    CAS  PubMed  Google Scholar 

  143. 143

    Arranz B, Cowburn R, Eriksson A, Vestling M, Marcusson J . Gamma-aminobutyric acid-B (GABAB) binding sites in postmortem suicide brains. Neuropsychobiology 1992; 26: 33–36.

    CAS  PubMed  Google Scholar 

  144. 144

    Stocks GM, Cheetham SC, Crompton MR, Katona CL, Horton RW . Benzodiazepine binding sites in amygdala and hippocampus of depressed suicide victims. J Affect Disord 1990; 18: 11–15.

    CAS  PubMed  Google Scholar 

  145. 145

    Sundman I, Allard P, Eriksson A, Marcusson J . GABA uptake sites in frontal cortex from suicide victims and in aging. Neuropsychobiology 1997; 35: 11–15.

    CAS  PubMed  Google Scholar 

  146. 146

    Korpi ER, Kleinman JE, Wyatt RJ . GABA concentrations in forebrain areas of suicide victims. Biol Psychiatry 1988; 23: 109–114.

    CAS  PubMed  Google Scholar 

  147. 147

    Benes FM, Todtenkopf MS, Logiotatos P, Williams M . Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain. J Chem Neuroanat 2000; 20: 259–269.

    CAS  PubMed  Google Scholar 

  148. 148

    Guidotti A, Auta J, Davis JM, DiGiorgi Gerevini V, Dwivedi Y, Grayson DR et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder. Arch Gen Psychiatry 2000; 57: 1061–1069.

    CAS  Google Scholar 

  149. 149

    Cotter D, Landau S, Beasley C, Stevenson R, Chana G, MacMillan L et al. The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive, disorder, bipolar disorder and schizophrenia. Biol Psychiatry 2002; 51: 377–386.

    CAS  PubMed  Google Scholar 

  150. 150

    Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes F . Differential expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry 2002; 59: 521–529.

    CAS  PubMed  Google Scholar 

  151. 151

    Honig A, Bartlett JR, Bouras N, Bridges PK . Amino acid levels in depression: a preliminary investigation. J Psychiatric Res 1988; 22: 159–164.

    CAS  Google Scholar 

  152. 152

    Northoff G, Steinke R, Czcervenka C, Krause R, Ulrich S, Danos P et al. Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding. J Neurol Neurosurg Psychiatry 1999; 67: 445–450.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA et al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999; 56: 1043–1047.

    CAS  Google Scholar 

  154. 154

    Sanacora G, Mason GF, Rothman DL, Krystal JH . Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 2002; 159: 663–665.

    PubMed  Google Scholar 

  155. 155

    Epperson CN, Haga K, Mason GF, Sellers E, Gueorguieva R, Zhang W et al. Cortical γ-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder. Arch Gen Psychiatry 2002; 59: 851–858.

    CAS  PubMed  Google Scholar 

  156. 156

    Soares JC, Mann JJ . The anatomy of mood disorders−review of structural neuroimaging studies. Biol Psychiatry 1997; 41: 86–106.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Brambilla P, Barale F, Caverzasi E, Soares JC . Anatomical MRI findings in mood and anxiety disorders. Epidemiol Psychiatr Soc 2002; 11: 88–99.

    Google Scholar 

  158. 158

    Gamse R, Vaccaro DE, Gamse G, DiPace M, Fox TO, Leeman SE . Release of immunoreactive somatostatin from hypothalamic cells in culture: inhibition by gamma-aminobutyric acid. Proc Natl Acad Sci USA 1980; 77: 5552–5556.

    CAS  PubMed  Google Scholar 

  159. 159

    Racagni G, Apud JA, Civati C, Cocchi D, Casanueva F, Locatelli V et al. Neurochemical aspects of GABA and glutamate in the hypothalamo-pituitary system. Adv Biochem Psychopharmacol 1981; 26: 261–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Koulu M, Lammintausta R, Dahlstrom S . Stimulatory effect of acute baclofen administration on human growth hormone secretion. J Clin Endocrinol Metab 1979; 48: 1038–1040.

    CAS  PubMed  Google Scholar 

  161. 161

    Shiah I-S, Yatham LN, Lam R, Tam EM, Zis PA . Growth hormone response to baclofen in patients with mania: a pilot study. Psychopharmacology 1999; 147: 280–284.

    CAS  PubMed  Google Scholar 

  162. 162

    Shiah I-S, Robertson HA, Lam R, Yatham LN, Tam EM, Zis PA . Growth hormone response to baclofen in patients with seasonal affective disorder: effects of light therapy. Psychoneuroendocrinology 1999; 24: 143–153.

    CAS  PubMed  Google Scholar 

  163. 163

    Marchesi C, Chiodera P, De Ferri A, De Risio C, Dasso L, Menozzi P et al. Reduction of GH response to the GABA-B agonist baclofen in patients with major depression. Psychoneuroendocrinology 1991; 16: 475–479.

    CAS  PubMed  Google Scholar 

  164. 164

    O'Flynn K, Dinan TG . Baclofen-induced growth hormone release in major depression: relationship to dexamethasone suppression test result. Am J Psychiatry 1993; 150: 1728–1730.

    CAS  PubMed  Google Scholar 

  165. 165

    Monteleone P, Maj M, Iovino M, Steardo L . GABA, depression and the mechanism of action of antidepressant drugs: a neuroendocrine approach. J Affect Disord 1990; 20: 1–5.

    CAS  PubMed  Google Scholar 

  166. 166

    Davis LL, Trivedi M, Choate A, Kramer GL, Petty F . Growth hormone response to the GABAB agonist baclofen in major depressive disorder. Psychoneuroendocrinology 1997; 22: 129–140.

    CAS  PubMed  Google Scholar 

  167. 167

    Heninger C, Saito N, Tallman JF, Garrett KM, Vitek MP, Duman RS et al. Effects of continuous diazepam administration on GABAA subunit mRNA in rat brain. J Mol Neurosci 1990; 2: 101–107.

    CAS  PubMed  Google Scholar 

  168. 168

    Kang I, Miller LG . Decreased GABAA receptor subunit mRNA concentrations following chronic lorazepam administration. Br J Pharmacol 1991; 103: 1285–1287.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Primus RJ, Gallager DW . GABAA receptor subunit mRNA levels are differentially influenced by chronic FG 7142 and diazepam exposure. Eur J Pharmacol 1992; 226: 21–28.

    CAS  PubMed  Google Scholar 

  170. 170

    Holt RA, Bateson AN, Martin IL . Chronic treatment with diazepam or abecarnil differently affects the expression of GABAA receptor subunit mRNAs in the rat cortex. Neuropharmacology 1996; 35: 1457–1463.

    CAS  PubMed  Google Scholar 

  171. 171

    Tanay VA, Glencorse TA, Greenshaw AJ, Baker GB, Bateson AN . Chronic administration of antipanic drugs alters rat brainstem GABAA receptor subunit mRNA levels. Neuropharmacology 1996; 35: 1475–1482.

    CAS  PubMed  Google Scholar 

  172. 172

    Wang J-F, Sun X, Chen B, Young LT . Lamotrigine increases gene expression of GABAA receptor β3 subunit in primary cultured rat hippocampus cells. Neuropsychopharmacology 2002; 26: 415–421.

    CAS  PubMed  Google Scholar 

  173. 173

    Lloyd KG, Thuret F, Pilc A . Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock. J Pharmacol Exp Ther 1985; 235: 191–199.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Motohashi N, Ikawa K, Kariya T . GABAB receptors are up-regulated by chronic treatment with lithium or carbamazepine. GABA hypothesis of affective disorders? Eur J Pharmacol 1989; 166: 95–99.

    CAS  PubMed  Google Scholar 

  175. 175

    Motohashi N . GABA receptor alterations after chronic lithium administration. Comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16: 571–579.

    CAS  PubMed  Google Scholar 

  176. 176

    Mendlewicz J . Population and family studies in depression and mania. Br J Psychiatry 1988; 1539Suppl 3): 16–25.

    Google Scholar 

  177. 177

    Oruc L, Verheyen GR, Furac I, Ivezic S, Jakovljevic M, Raeymaekers P et al. Positive association between the GABRA5 gene and unipolar recurrent major depression. Neuropsychobiology 1997; 36: 62–64.

    CAS  PubMed  Google Scholar 

  178. 178

    Papadimitriou GN, Dikeos DG, Karadima G, Avramopoulos D, Daskalopoulou EG, Vassilopoulos D et al. Association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) and bipolar affective disorder. Am J Med Genet 1998; 81: 73–80.

    CAS  PubMed  Google Scholar 

  179. 179

    Massat I, Souery D, Del-Favero J, Van Gestel S, Van Broeckhoven C, Mendlewicz J . GABRA1 receptor polymorphism and unipolar affective disorder: evidence for a protective gene in a European multicenter association study of affective disorders. Eur Neuropsychopharmacol 2001; 11(Suppl 1): 19.

    Google Scholar 

  180. 180

    Massat I, Souery D, Del-Favero J, Oruc L, Noethen MM, Blackwood D et al. Excess of allel1 for 3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study. Mol Psychiatry 2002; 7: 201–207.

    CAS  PubMed  Google Scholar 

  181. 181

    De Bruyn A, Sourey D, Mendelbaum K, Mendlewicz J, Van Broeckhoven C . A linkage study between bipolar disorder and genes involved in dopaminergic and GABAergic neurotransmission. Psychiatr Genet 1996; 6: 67–73.

    CAS  PubMed  Google Scholar 

  182. 182

    Ewald H, Mors O, Flint T, Kruse TA . Linkage analysis between manic-depressive illness and the region on chromosome 15q involved in Prader-Willi syndrome, including two GABA A receptor subtype genes. Human Hered 1994; 44: 287–294.

    CAS  Google Scholar 

  183. 183

    Walsh C, Hicks A, Sham P . GABAA receptor subunit genes as candidate genes for bipolar affective disorder: an association analysis. Psychiatr Genet 1992; 2: 239–247.

    Google Scholar 

  184. 184

    Puertollano R, Visedo G, Saiz-Ruiz J, Llinares C, Fernandez-Piqueras J . Lack of association between manic-depressive illness and a highly polymorphic marker from GABRA3 gene. Am J Med Genet 1995; 60: 434–435.

    CAS  Google Scholar 

  185. 185

    Duffy A, Turecki G, Grof P, Cavazzoni P, Grof E, Joober R et al. Association and linkage studies of candidate genes involved in GABAergic neurotransmission in lithium-responsive bipolar disorder. J Psychiatry Neurosci 2000; 25: 353–358.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Coon H, Hicks AA, Bailey ME, Hoff M, Holik J, Harvey RJ et al. Analysis of GABAA receptor subunit genes in multiplex pedigrees with manic depression. Psychiatr Genet 1994; 4: 185–191.

    CAS  PubMed  Google Scholar 

  187. 187

    Papadimitriou GN, Dikeos DG, Karadima G, Avramopoulos D, Daskalopoulou EG, Stefanis CN . GABA-A receptor β3 and α5 subunit gene cluster on chromosome 15q11−q13 and bipolar disorder: a genetic association study. Am J Med Genetics 2001; 105: 317–320.

    CAS  Google Scholar 

  188. 188

    Oruc L, Furac I, Croux C, Jakovljevic M, Kracun I, Folnegovic V et al. Association study between bipolar disorder and candidate genes involved in dopamine−serotonin metabolism and GABAergic neurotransmission: a preliminary report. Psychiatr Genet 1996; 6: 213–217.

    CAS  Google Scholar 

  189. 189

    Puertollano R, Visedo G, Zapata C, Fernandez-Piqueras J . A study of genetic association between manic-depressive illness and a highly polymorphic marker from the GABRβ-1 gene. Am J Med Gen 1997; 74: 342–344.

    CAS  Google Scholar 

  190. 190

    Bernasconi R . The GABA hypothesis of affective illness: influence of clinically effective antimanic drugs on GABA turnover. In: Emrich HD, Aldenhoff HD, Lux HD (eds). Excerpta Medica. Amsterdam, 1982, pp. 183–191.

    Google Scholar 

  191. 191

    Loscher W . Valproate enhances GABA turnover in the substantia nigra. Brain Res 1989; 501: 198–203.

    CAS  PubMed  Google Scholar 

  192. 192

    Cunningham MO, Jones RS . The anticonvulsant lamotrigine decreases spontaneous gluatamate release but increases spontaneous GABA release in the rat enthorinal cortex in vitro. Neuropharmacology 2000; 39: 2139–2146.

    CAS  Google Scholar 

  193. 193

    Hassel B, Tauboll E, Gjerstad L . Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels. Epilepsy Res 2001; 43: 153–163.

    CAS  PubMed  Google Scholar 

  194. 194

    Otero Losada ME, Rubio MC . Acute and chronic effects of lithium chloride on GABA-ergic function in the rat corpus striatum and frontal cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol 1986; 332: 169–172.

    CAS  PubMed  Google Scholar 

  195. 195

    Ahluwalia P, Grewaal DS, Singhal RL . Brain GABAergic and dopaminergic systems following lithium treatment and withdrawal. Prog Neuropsychopharmacol 1981; 5: 527–530.

    CAS  PubMed  Google Scholar 

  196. 196

    Gottesfeld Z . Effect of lithium and other alkali metals on brain chemistry and behavior. I. Glutamic acid and GABA in brain regions. Psychopharmacologia 1976; 45: 239–242.

    CAS  PubMed  Google Scholar 

  197. 197

    Weiss S, Kemp DE, Bauce L, Tse FW . Kainate receptors coupled to the evoked release of [3H]-gamma-aminobutyric acid from striatal neurons in primary culture: potentiation by lithium ions. Mol Pharmacol 1990; 38: 229–236.

    CAS  PubMed  Google Scholar 

  198. 198

    Maggi A, Enna SJ . Regional alterations in rat brain neurotransmitter systems following chronic lithium treatment. J Neurochem 1980; 34: 888–892.

    CAS  PubMed  Google Scholar 

  199. 199

    Vargas C, Tannhauser M, Barros HM . Dissimilar effects of lithium and valproic acid on GABA and glutamine concentrations in rat cerebrospinal fluid. Gen Pharmacol 1998; 30: 601–604.

    CAS  PubMed  Google Scholar 

  200. 200

    Iadarola MJ, Raines A, Gale K . Differential effects of n-dipropylacetate and amino-oxyacetic acid on gamma-aminobutyric acid levels in discrete areas of rat brain. J Neurochem 1979; 33: 1119–1123.

    CAS  PubMed  Google Scholar 

  201. 201

    Loscher W, Vetter M . In vivo effects of aminooxyacetic acid and valproic acid on nerve terminal (synaptosomal) GABA levels in discrete brain areas of the rat. Correlation to pharmacological activities. Biochem Pharmacol 1985; 34: 1747–1756.

    CAS  PubMed  Google Scholar 

  202. 202

    Loscher W, Horstermann D . Differential effects of vigabatrin, gamma-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma. Naunyn Schmiedebergs Arch Pharmacol 1994; 349: 270–278.

    CAS  PubMed  Google Scholar 

  203. 203

    Gram L, Larsson OM, Johnsen AH, Schousboe A . Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons. Epilepsy Res 1988; 2: 87–95.

    CAS  PubMed  Google Scholar 

  204. 204

    Phillips NI, Fowler LJ . The effects of sodium valproate on gamma-aminobutyrate metabolism and behaviour in naive and ethanolamine-O-sulphate pretreated rats and mice. Biochem Pharmacol 1982; 31: 2257–2261.

    CAS  PubMed  Google Scholar 

  205. 205

    Macdonald RL, Bergey GK . Valproic acid augments GABA-mediated postsynaptic inhibition in cultured mammalian neurons. Brain Res 1979; 170: 558–562.

    CAS  PubMed  Google Scholar 

  206. 206

    Loscher W . Effect of inhibitors of GABA transaminase on the synthesis, binding, uptake, and metabolism of GABA. J Neurochem 1980; 34: 1603–1608.

    CAS  PubMed  Google Scholar 

  207. 207

    Larsson OM, Gram L, Schousboe I, Schousboe A . Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurones and astrocytes. Neuropharmacology 1986; 25: 617–625.

    CAS  PubMed  Google Scholar 

  208. 208

    Loscher W, Schmidt D . Increase of human plasma GABA by sodium valproate. Epilepsia 1980; 21: 611–615.

    CAS  PubMed  Google Scholar 

  209. 209

    Loscher W, Schmidt D . Plasma GABA levels in neurological patients under treatment with valproic acid. Life Sci 1981; 28: 283–288.

    CAS  PubMed  Google Scholar 

  210. 210

    Shiah IS, Yatham LN, Baker GB . Divalproex sodium increases plasma GABA levels in healthy volunteers. Int Clin Psychopharmacol 2000; 15: 221–225.

    CAS  PubMed  Google Scholar 

  211. 211

    Post RM, Ballenger JC, Hare TA, Bunney Jr WE . Lack of effect of carbamazepine on gamma-aminobutyric acid in cerebrospinal fluid. Neurology 1980; 30: 1008–1011.

    CAS  PubMed  Google Scholar 

  212. 212

    Prevett MC, Lammertsma AA, Brooks DJ, Bartenstein PA, Patsalos PN, Fish DR et al. Benzodiazepine-GABAA receptors in idiopathic generalized epilepsy measured with [11C]flumazenil and positron emission tomography. Epilepsia 1995; 36: 113–121.

    CAS  PubMed  Google Scholar 

  213. 213

    Petroff OA, Rothman DL, Behar KL, Lamoureux D, Mattson RH . The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 1996; 39: 95–99.

    CAS  Google Scholar 

  214. 214

    Kuzniecky R, Hetherington H, Ho S, Pan J, Martin R, Gilliam F et al. Topiramate increases cerebral GABA in healthy humans. Neurology 1998; 51: 627–629.

    CAS  PubMed  Google Scholar 

  215. 215

    Verhoeff NP, Petroff OA, Hyder F, Zoghbi SS, Fujita M, Rajeevan N et al. Effects of vigabatrin on the GABAergic system as determined by [123I]iomazenil SPECT and GABA MRS. Epilepsia 1999; 40: 1433–1438.

    CAS  PubMed  Google Scholar 

  216. 216

    Brambilla P, Barale F, Soares JC . Perspectives on the use of anticonvulsants in the treatment of bipolar disorder. Int J Neuropsychopharmacol 2001; 4: 421–446.

    CAS  PubMed  Google Scholar 

  217. 217

    Shiah IS, Yatham LN, Lam RW, Zis AP . Divalproex sodium attenuates growth hormone response to baclofen in healthy human males. Neuropsychopharmacology 1998; 18: 370–376.

    CAS  PubMed  Google Scholar 

  218. 218

    Serretti A, Lilli R, Lorenzi C, Franchini L, Di Bella D, Catalano M et al. Dopamine receptor D2 and D4 genes, GABA(A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders. Psychiatry Res 1999; 87: 7–19.

    CAS  PubMed  Google Scholar 

  219. 219

    Suranyi-Cadotte BE, Dam TV, Quirion R . Antidepressant-−anxiolytic interaction: decreased density of benzodiazepine receptors in rat brain following chronic administration of antidepressants. Eur J Pharmacol 1984; 106: 673–675.

    CAS  PubMed  Google Scholar 

  220. 220

    Barbaccia ML, Ravizza L, Costa E . Maprotiline. An antidepressant with an unusual pharmacological profile. J Pharmacol Exp Ther 1986; 236: 307–312.

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221

    Bouthillier A, de Montigny C . Long-term antidepressant treatment reduces neuronal responsiveness to flurazepam: an electrophysiological study in the rat. Neurosci Lett 1987; 73: 271–275.

    CAS  PubMed  Google Scholar 

  222. 222

    Pilc A, Lloyd KG . Chronic antidepressants and GABA receptors: a GABA hypothesis of antidepressant drug action. Life Sci 1984; 35: 2149–2254.

    CAS  PubMed  Google Scholar 

  223. 223

    Kimber JR,, Cross JA, Horton RW . Benzodiazepine and GABAA receptors in rat brain following chronic antidepressant drug administration. Biochem Pharmacol 1987; 36: 4173–4175.

    CAS  PubMed  Google Scholar 

  224. 224

    McKenna KF, McManus DJ, Baker GB, Coutts RT . Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: effects on GABAergic function. J Neural Transm Suppl 1994; 41: 115–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225

    Todd KG, McManus DJ, Baker GB . Chronic administration of the antidepressants phenelzine, desipramine, clomipramine, or maprotiline decreases binding to 5-hydroxytryptamine2A receptors without affecting benzodiazepine binding sites in rat brain. Cell Mol Neurobiol 1995; 15: 361–370.

    CAS  PubMed  Google Scholar 

  226. 226

    Suzdak PD, Gianutsos G . Effect of chronic imipramine or baclofen on GABA-B binding and cyclic AMP production in cerebral cortex. Eur J Pharmacol 1986; 131: 129–133.

    CAS  PubMed  Google Scholar 

  227. 227

    Pratt GD, Bowery NG . Repeated administration of desipramine and a GABAB receptor antagonist, CGP 36742, discretely up-regulates GABAB receptor binding sites in rat frontal cortex. Br J Pharmacol 1993; 110: 724–735.

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228

    Szekely AM, Barbaccia ML, Costa E . Effect of a protracted antidepressant treatment on signal transduction and [3H](-)-baclofen binding at GABAB receptors. J Pharmacol Exp Ther 1987; 243: 155–159.

    CAS  PubMed  Google Scholar 

  229. 229

    Cross JA, Horton RW . Are increases in GABAB receptors consistent findings following chronic antidepressant administration? Eur J Pharmacol 1987; 141: 159–162.

    CAS  PubMed  Google Scholar 

  230. 230

    McManus DJ, Greenshaw AJ . Differential effects of antidepressants on GABAB and beta-adrenergic receptors in rat cerebral cortex. Biochem Pharmacol 1991; 42: 1525–1528.

    CAS  PubMed  Google Scholar 

  231. 231

    Engelbrecht AH, Russell VA, Taljaard JJ . Lack of effect of bilateral locus coeruleus lesion and antidepressant treatment on gamma-aminobutyric acidB receptors in the rat frontal cortex. Neurochem Res 1994; 19: 1119–1123.

    CAS  PubMed  Google Scholar 

  232. 232

    Gray JA, Green AR . Increased GABAB receptor function in mouse frontal cortex after repeated administration of antidepressant drugs or electroconvulsive shocks. Br J Pharmacol 1987; 92: 357–362.

    CAS  PubMed  PubMed Central  Google Scholar 

  233. 233

    Gray JA, Green AR . GABAB-receptor mediated inhibition of potassium-evoked release of endogenous 5-hydroxytryptamine from mouse frontal cortex. Br J Pharmacol 1987; 91: 517–522.

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J et al. (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 1980; 283: 92–94.

    CAS  PubMed  Google Scholar 

  235. 235

    Borsini F, Giuliani S, Meli A . Functional evidence for altered activity of GABAergic receptors following chronic desipramine treatment in rats. J Pharm Pharmacol 1986; 38: 934–935.

    CAS  PubMed  Google Scholar 

  236. 236

    McManus DJ, Greenshaw AJ . Differential effects of chronic antidepressants in behavioural tests of beta-adrenergic and GABAB receptor function. Psychopharmacology 1991; 103: 204–208.

    CAS  PubMed  Google Scholar 

  237. 237

    Baker GB, Wong JT, Yeung JM, Coutts RT . Effects of the antidepressant phenelzine on brain levels of gamma-aminobutyric acid (GABA). J Affect Disord 1991; 21: 207–211.

    CAS  PubMed  Google Scholar 

  238. 238

    McManus DJ, Baker GB, Martin IL, Greenshaw AJ, McKenna KF . Effects of the antidepressant/antipanic drug phenelzine on GABA concentrations and GABA-transaminase activity in rat brain. Biochem Pharmacol 1992; 43: 2486–2489.

    CAS  PubMed  Google Scholar 

  239. 239

    Paslawski TM, Sloley BD, Baker GB . Effects of the MAO inhibitor phenelzine on glutamine and GABA concentrations in rat brain. Prog Brain Res 1995; 106: 181–186.

    CAS  PubMed  Google Scholar 

  240. 240

    Parent M, Habib MK, Baker GB . Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine. Biochem Pharmacol 2000; 59: 1253–1263.

    CAS  PubMed  Google Scholar 

  241. 241

    Lai CT, Tanay VA, Charrois GJ, Baker GB, Bateson AN . Effects of phenelzine and imipramine on the steady-state levels of mRNAs that encode glutamic acid decarboxylase (GAD67 and GAD65), the GABA transporter GAT-1 and GABA transaminase in rat cortex. Naunyn Schmiedebergs Arch Pharmacol 1998; 357: 32–38.

    CAS  PubMed  Google Scholar 

  242. 242

    Korf J, Venema K . Desmethylimipramine enhances the release of endogenous GABA and other neurotransmitter amino acids from the rat thalamus. J Neurochem 1983; 40: 946–950.

    CAS  PubMed  Google Scholar 

  243. 243

    Giardino L, Zanni M, Bettelli C, Savina MA, Calza L . Regulation of glutamic acid decarboxylase mRNA expression in rat brain after sertraline treatment. Eur J Pharmacol 1996; 312: 183–187.

    CAS  PubMed  Google Scholar 

  244. 244

    Herman JP, Renda A, Bodie B . Norepinephrine–gamma-aminobutyric acid (GABA) interaction in limbic stress circuits: effects of reboxetine on GABAergic neurons. Biol Psychiatry 2003; 53: 166–174.

    CAS  PubMed  Google Scholar 

  245. 245

    Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D . St John's Wort for depression—an overview and meta-analysis of randomised clinical trials. BMJ 1996; 313: 253–258.

    CAS  PubMed  PubMed Central  Google Scholar 

  246. 246

    Wonnemann M, Singer A, Muller WE . Inhibition of synaptosomal uptake of 3H-L-glutamate and 3H-GABA by hyperforin, a major constituent of St. John's Wort: the role of amiloride sensitive sodium conductive pathways. Neuropsychopharmacology 2000; 23: 188–197.

    CAS  PubMed  Google Scholar 

  247. 247

    Griffin LD, Mellon SH . Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA. 1999; 96: 13512–13517.

    CAS  PubMed  Google Scholar 

  248. 248

    Khisti RT, Chopde CT . Serotonergic agents modulate antidepressant-like effect on the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one in mice. Brain Res 2000; 865: 291–300.

    CAS  PubMed  Google Scholar 

  249. 249

    Khisti RT, Chopde CT, Jain SP . Antidepressant-like effect of the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one in mice forced swim test. Pharmacol Biochem Behav 2000; 67: 137–143.

    CAS  PubMed  Google Scholar 

  250. 250

    Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B, Holsboer F et al. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry 1998; 155: 910–913.

    CAS  PubMed  Google Scholar 

  251. 251

    Strohle A, Romeo E, Hermann B, Pasini A, Spalletta G, di Michele F et al. Concentrations of 3 alpha-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry 1999; 45: 274–277.

    CAS  PubMed  Google Scholar 

  252. 252

    Strohle A, Pasini A, Romeo E, Hermann B, Spalletta G, di Michele F et al. Fluoxetine decreases concentrations of 3 alpha, 5 alpha-tetrahydrodeoxy-corticosterone (THDOC) in major depression. J Psychiatr Res 2000; 34: 183–186.

    CAS  PubMed  Google Scholar 

  253. 253

    Monteleone P, Steardo L, Tanzillo C, Maj M . Chronic antidepressant drug treatment does not affect GH response to baclofen in depressed subjects. J Neural Transm Gen Sect 1990; 82: 147–152.

    CAS  PubMed  Google Scholar 

  254. 254

    Lavoie AM, Twyman RE . Direct evidence for diazepam modulation of GABAA receptor microscopic affinity. Neuropharmacology 1996; 35: 1383–1392.

    CAS  PubMed  Google Scholar 

  255. 255

    Obata T, Morelli M, Concas A, Serra M, Yamamura HI . Modulation of GABA-stimulated chloride influx into membrane vesicles from rat cerebral cortex by benzodiazepines and nonbenzodiazepines. Adv Biochem Psychopharmacol 1988; 45: 175–187.

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256

    Loscher W, Schmidt D . Diazepam increases gamma-aminobutyric acid in human cerebrospinal fluid. J Neurochem 1987; 49: 152–157.

    CAS  PubMed  Google Scholar 

  257. 257

    Roy-Byrne PP, Cowley DS, Hommer D, Greenblatt DJ, Kramer GL, Petty F . Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls. Psychopharmacology 1992; 109: 153–156.

    CAS  PubMed  Google Scholar 

  258. 258

    de Wit H, Metz J, Wagner N, Cooper M . Effects of diazepam on cerebral metabolism and mood in normal volunteers. Neuropsychopharmacology. 1991; 5: 33–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259

    Matthew E, Andreason P, Pettigrew K, Carson RE, Herscovitch P, Cohen R et al. Benzodiazepine receptors mediate regional blood flow changes in the living human brain. Proc Natl Acad Sci USA 1995; 92: 2775–2779.

    CAS  PubMed  Google Scholar 

  260. 260

    Fujita M, Woods SW, Verhoeff NP, Abi-Dargham A, Baldwin RM, Zoghbi SS et al. Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Eur J Pharmacol 1999; 368: 161–172.

    CAS  PubMed  Google Scholar 

  261. 261

    Wang GJ, Volkow ND, Overall J, Hitzemann RJ, Pappas N, Pascani K et al. Reproducibility of regional brain metabolic responses to lorazepam. J Nucl Med 1996; 37: 1609–1613.

    CAS  PubMed  PubMed Central  Google Scholar 

  262. 262

    Brambilla P, Soares JC . The pharmacological treatment of acute mania. In: Dunner DL, Rosenbaum J (eds). Psychiatric Clinics of North America: Annual of Drug Therapy. W.B. Saunders Company: Philadelphia, PA, 2001, Vol. 8, pp. 155–180.

    Google Scholar 

  263. 263

    Kishimoto A, Kamata K, Sugihara T, Ishiguro S, Hazama H, Mizukawa R et al. Treatment of depression with clonazepam. Acta Psychiatr Scand 1988; 77: 81–86.

    CAS  PubMed  Google Scholar 

  264. 264

    Rush AJ, Schlesser MA, Erman M, Fairchild C . Alprazolam in bipolar-I depressions. Pharmacotherapy 1984; 4: 40–42.

    CAS  PubMed  Google Scholar 

  265. 265

    Dunner D, Myers J, Khan A, Avery D, Ishiki D, Pyke R . Adinazolam-a new antidepressant: findings of a placebo-controlled, double-blind study in outpatients with major depression. J Clin Psychopharmacol 1987; 7: 170–172.

    CAS  PubMed  Google Scholar 

  266. 266

    Jonas JM, Cohon MS . A comparison of the safety and efficacy of alprazolam versus other agents in the treatment of anxiety, panic, and depression: a review of the literature. J Clin Psychiatry 1993; 54 (Supp 2): 25–45.

    PubMed  Google Scholar 

  267. 267

    Farnbach-Pralong D, Bradbury R, Copolov D, Dean B . Clozapine and olanzapine treatment decreases rat cortical and limbic GABA(A) receptors. Eur J Pharmacol 1998; 349: R7–R8.

    CAS  PubMed  Google Scholar 

  268. 268

    Bourdelais AJ, Deutch AY . The effects of haloperidol and clozapine on extracellular GABA levels in the prefrontal cortex of the rat: an in vivo microdialysis study. Cerebr Cort 1994; 4: 69–77.

    CAS  Google Scholar 

  269. 269

    See RF, Berglind WJ, Krentz L, Meshul CK . Convergent evidence from microdialysis and presynaptic immunolabeling for the regulation of gamma-aminobutyric acid release in the globus pallidus following acute clozapine or haloperidol administration in rats. J Neurochem 2002; 82: 172–180.

    CAS  PubMed  Google Scholar 

  270. 270

    Brambilla, Barale F, Soares JC . Atypical antipsychotics and mood stabilization in bipolar disorder. Psychopharmacology 2003; 166: 315–332.

    CAS  PubMed  Google Scholar 

  271. 271

    Fink M . Convulsive therapy: a review of the first 55 years. J Affect Disord 2001; 63: 1–15.

    CAS  PubMed  Google Scholar 

  272. 272

    Wielosz M, Stelmasiak M, Ossowska G, Kleinrok Z . Effects of electroconvulsive shock on central GABA-ergic mechanisms. Pol J Pharmacol Pharm 1985; 37: 113–122.

    CAS  PubMed  Google Scholar 

  273. 273

    Green AR, Metz A, Minchin MC, Vincent ND . Inhibition of the rate of GABA synthesis in regions of rat brain following a convulsion. Br J Pharmacol 1987; 92: 5–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  274. 274

    Bowdler JM, Green AR, Minchin MC, Nutt DJ . Regional GABA concentration and [3H]-diazepam binding in rat brain following repeated electroconvulsive shock. J Neural Transm 1983; 56: 3–12.

    CAS  PubMed  Google Scholar 

  275. 275

    Green AR, Vincent ND . The effect of repeated electroconvulsive shock on GABA synthesis and release in regions of rat brain. Br J Pharmacol 1987; 92: 19–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  276. 276

    Chabannes J, Baro P, Lambert P, Decade P, Musch B . Antidepressant activity of fengabide (SL 79229): results from an open pilot study. In: Bartholini G, Lloyd K, Morselli P (eds). GABA and Mood Disorders: Experimental and Clinical Research. Raven Press: New York, 1986.

    Google Scholar 

  277. 277

    Mendlewicz J, Linkowski P, Coupez-Lopinot R . Treatment of depressed patients with fengabide (SL 79229): preliminary results. In: Bartholini G, Lloyd K, Morselli P (eds). GABA and Mood Disorders: Experimental and Clinical Research. Raven Press: New York, 1986.

    Google Scholar 

  278. 278

    Muscettola G, Casiello M, Giannini C, Bossi L . Pilot study of progabide in depression. In: Bartholini G, Lloyd K, Morselli P (eds). GABA and Mood Disorders: Experimental and Clinical Research. Raven Press: New York, 1986.

    Google Scholar 

  279. 279

    Perris C, Tjallden G, Bossi L, Perris H . Progabide versus nortriptiline in depression: a controlled trial. In: Bartholini G, Lloyd K, Morselli P (eds). GABA and Mood Disorders: Experimental and Clinical Research. Raven Press: New York, 1986.

    Google Scholar 

  280. 280

    Weiss E, Brunner H, Clerc G, Guibert M, Orofiamma B, Pagot R et al. Multicenter double-blind study of progabide in depressed patients. In: Bartholini G, Lloyd K, Morselli P (eds). GABA and Mood Disorders: Experimental and Clinical Research. Raven Press: New York, 1986.

    Google Scholar 

  281. 281

    Nielsen NP, Cesana B, Zizolfi S, Ascalone V, Priore P, Morselli PL . Therapeutic effects of fengabine, a new GABAergic agent, in depressed outpatients: a double-blind study versus clomipramine. Acta Psychiatr Scand 1990; 82: 366–371.

    CAS  PubMed  Google Scholar 

  282. 282

    Petty F, Trivedi MH, Fulton M, Rush AJ . Benzodiazepines as antidepressants: does GABA play a role in depression? Biol Psychiatry 1995; 38: 578–591.

    CAS  PubMed  Google Scholar 

  283. 283

    Blum BP, Mann JJ . The GABAergic system in schizophrenia. Int J Neuropsychopharmacol 2002; 5: 159–179.

    CAS  PubMed  Google Scholar 

  284. 284

    Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ . Decreased brain GABA(A) −benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998; 55: 715–720.

    CAS  PubMed  Google Scholar 

  285. 285

    Bremner JD, Innis RB, White T, Fujita M, Silbersweig D, Goddard AW et al. SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry 2000; 47: 96–106.

    CAS  PubMed  Google Scholar 

Download references


This work was partly supported by the National Institute of Mental Health (MH 01736), NARSAD, and the Veterans Administration. Dr Brambilla was supported by grants from the University of Pavia and from the Fatebenefratelli-Brescia (Ministry of Health). We thank A Mangiò ( for great help with the figure.

Author information



Corresponding author

Correspondence to P Brambilla.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brambilla, P., Perez, J., Barale, F. et al. GABAergic dysfunction in mood disorders. Mol Psychiatry 8, 721–737 (2003).

Download citation


  • GABA
  • bipolar disorder
  • unipolar disorder
  • mood disorders
  • antidepressants
  • mood stabilizers

Further reading


Quick links