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GABAergic dysfunction in mood disorders

Abstract

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.

Main

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
figure1

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

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

Antipsychotics

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.

Conclusions

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.

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Acknowledgements

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 (amangio@artechvideo.it) for great help with the figure.

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Brambilla, P., Perez, J., Barale, F. et al. GABAergic dysfunction in mood disorders. Mol Psychiatry 8, 721–737 (2003). https://doi.org/10.1038/sj.mp.4001362

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Keywords

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

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