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.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
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.
Meldrum B . Pharmacology of GABA. Clin Neuropharmacol 1982; 5: 293–316.
Guidotti A, Corda MG, Wise BC, Vaccarino F, Costa E . GABAergic synapses. Supramolecular organization and biochemical regulation. Neuropharmacology 1983; 22: 1471–1479.
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.
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.
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.
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.
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.
Borden LA . GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int 1996; 29: 335–356.
Cherubini E, Conti F . Generating diversity at GABAergic synapses. Trends Neurosci 2001; 24: 155–162.
Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ . Two genes encode distinct glutamate decarboxylases. Neuron 1991; 7: 91–100.
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.
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.
Bormann J . Electrophysiology of GABAA and GABAB receptor subtypes. Trends Neurosci 1988; 11: 112–116.
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.
Haefely W, Kulcsar A, Mohler H . Possible involvement of GABA in the central actions of benzodiazepines. Psychopharmacol Bull 1975; 11: 58–59.
Nicoll RA, Eccles JC, Oshima T, Rubia F . Prolongation of hippocampal inhibitory postsynaptic potentials by barbiturates. Nature 1975; 258: 625–627.
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.
Mhatre M, Ticku MK . Chronic ethanol treatment upregulates the GABA receptor beta subunit expression. Brain Res Mol Brain Res 1994; 23: 246–252.
Curtis DR, Duggan AW, Felix D, Johnston GA . Bicuculline and central GABA receptors. Nature 1970; 228: 676–677.
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.
Karbon EW, Duman RS, Enna SJ . GABAB receptors and norepinephrine-stimulated cAMP production in rat brain cortex. Brain Res 1984; 306: 327–332.
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.
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.
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.
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.
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.
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.
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.
Garbutt JC, van Kammen DP . The interaction between GABA and dopamine: implications for schizophrenia. Schizophr Bull 1983; 9: 336–353.
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.
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.
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.
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.
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.
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.
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.
Wang X, Zhong P, Yan Z . Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. J Neurosci 2002; 22: 9185–9193.
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.
Biswas B, Carlsson A . The effect of intracerebroventricularly administered GABA on brain monoamine metabolism. Naunyn Schmiedebergs Arch Pharmacol 1977; 299: 41–46.
Biswas B, Carlsson A . The effect of intraperitoneally administered GABA on brain monoamine metabolism. Naunyn Schmiedebergs Arch Pharmacol 1977; 299: 47–51.
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.
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.
Suzdak PD, Gianutsos G . Differential coupling of GABA-A and GABA-B receptors to the noradrenergic system. J Neural Transm 1985; 62: 77–89.
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.
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.
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.
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.
Mitoma H, Konishi S . Monoaminergic long-term facilitation of GABA-mediated inhibitory transmission at cerebellar synapses. Neuroscience 1999; 88: 871–883.
Nishikawa T, Scatton B . Evidence for a GABAergic inhibitory influence on serotonergic neurons originating from the dorsal raphe. Brain Res 1983; 279: 325–329.
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.
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.
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.
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.
Shen RY, Andrade R . 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J Pharmacol Exp Ther 1998; 285: 805–812.
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.
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.
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.
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.
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.
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.
Maggi A, Perez J . Role of female gonadal hormones in the CNS: clinical and experimental aspects. Life Sci 1985; 37: 893–906.
Perez J, Zucchi A, Maggi A . Sexual dimorphism in the response of the GABAergic system to estrogen administration. J Neurochem 1986; 47: 1798–1803.
McEwen BS . Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci 1991; 12: 141–147.
van Broekhoven F, Verkes RJ . Neurosteroids in depression: a review. Psychopharmacology 2003; 165: 97–110.
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.
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.
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.
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.
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.
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.
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.
Seligman ME, Maier SF . Failure to escape traumatic shock. J Exp Psychol 1967; 74: 1–9.
Sherman AD, Petty F . Neurochemical basis of the action of antidepressants on learned helplessness. Behav Neural Biol 1980; 30: 119–134.
Petty F, Sherman AD . GABAergic modulation of learned helplessness. Pharmacol Biochem Behav 1981; 15: 567–570.
Sherman AD, Petty F . Additivity of neurochemical changes in learned helplessness and imipramine. Behav Neural Biol 1982; 35: 344–353.
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.
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.
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.
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.
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.
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.
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.
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.
Guidotti A, Ferrero P, Costa E . On the brain endocoid for benzodiazepine recognition sites. Prog Clin Biol Res 1985; 192: 477–484.
Kelly JP, Wrynn AS, Leonard BE . The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther 1997; 74: 299–316.
Jancsar SM, Leonard BE . Changes in neurotransmitter metabolism following olfactory bulbectomy in the rat. Prog Neuropsychopharmacol Biol Psychiatry 1984; 8: 263–269.
Lloyd KG, Pichat P . Decrease in GABAB binding to the frontal cortex of olfactory bulbectomized rats. Br J Pharmacol 1986; 87: 36.
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.
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.
Leonard BE, Tuite M . Anatomical, physiological, and behavioral aspects of olfactory bulbectomy in the rat. Int Rev Neurobiol 1981; 22: 251–286.
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.
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.
Loscher W . Relationship between GABA concentrations in cerebrospinal fluid and seizure excitability. J Neurochem 1982; 38: 293–295.
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.
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.
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.
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.
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.
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.
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.
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.
Petty F, Kramer G, Feldman M . Is plasma GABA of peripheral origin? Biol Psychiatry 1987; 22: 725–732.
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.
Ferkany JW, Smith LA, Seifert WE, Caprioli RM, Enna SJ . Measurement of gamma-aminobutyric acid (GABA) in blood. Life Sci 1978; 22: 2121–2128.
Bohlen P, Huot S, Palfreyman MG . The relationship between GABA concentrations in brain and cerebrospinal fluid. Brain Res 1979; 167: 297–305.
Ferkany JW, Butler IJ, Enna SJ . Effect of drugs on rat brain, cerebrospinal fluid and blood GABA content. J Neurochem 1979; 33: 29–33.
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.
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.
Loscher W, Frey HH . Transport of GABA at the blood−CSF interface. J Neurochem 1982; 38: 1072–1079.
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.
Loscher W, Rating D, Siemes H . GABA in cerebrospinal fluid of children with febrile convulsions. Epilepsia 1981; 22: 697–702.
Schmidt D, Loscher W . Plasma and cerebrospinal fluid gamma-aminobutyric acid in neurological disorders. J Neurol Neurosurg Psychiatry 1982; 45: 931–935.
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.
Petty F, Schlesser MA . Plasma GABA in affective illness. A preliminary investigation. J Affect Disord 1981; 3: 339–343.
Petty F, Sherman AD . Plasma GABA levels in psychiatric illness. J Affect Disord 1984; 6: 131–138.
Petty F, Kramer GL, Dunnam D, Rush AJ . Plasma GABA in mood disorders. Psychopharmacol Bull 1990; 26: 157–161.
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.
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.
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.
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.
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.
Petty F, Kramer G . Stability of plasma gamma-aminobutyric acid with time in healthy controls. Biol Psychiatry 1992; 31: 743–745.
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.
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.
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.
Kaiya H, Namba M, Yoshida H, Nakamura S . Plasma glutamate decarboxylase activity in neuropsychiatry. Psychiatry Res 1982; 6: 335–343.
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.
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.
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.
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.
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.
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.
Yonkers KA . The association between premenstrual dysphoric disorder and other mood disorders. J Clin Psychiatry 1997; 58 (Suppl 15): 19–25.
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.
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.
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.
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.
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.
Cheetham SC, Crompton MR, Katona CLE, Horton RW . Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 1988; 443: 272–280.
Cross JA, Cheetham SC, Crompton MR, Katona CL, Horton RW . Brain GABAB binding sites in depressed suicide victims. Psychiatry Res 1988; 26: 119–129.
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.
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.
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.
Korpi ER, Kleinman JE, Wyatt RJ . GABA concentrations in forebrain areas of suicide victims. Biol Psychiatry 1988; 23: 109–114.
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.
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.
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.
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.
Honig A, Bartlett JR, Bouras N, Bridges PK . Amino acid levels in depression: a preliminary investigation. J Psychiatric Res 1988; 22: 159–164.
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.
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.
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.
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.
Soares JC, Mann JJ . The anatomy of mood disorders−review of structural neuroimaging studies. Biol Psychiatry 1997; 41: 86–106.
Brambilla P, Barale F, Caverzasi E, Soares JC . Anatomical MRI findings in mood and anxiety disorders. Epidemiol Psychiatr Soc 2002; 11: 88–99.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Kang I, Miller LG . Decreased GABAA receptor subunit mRNA concentrations following chronic lorazepam administration. Br J Pharmacol 1991; 103: 1285–1287.
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.
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.
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.
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.
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.
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.
Motohashi N . GABA receptor alterations after chronic lithium administration. Comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16: 571–579.
Mendlewicz J . Population and family studies in depression and mania. Br J Psychiatry 1988; 1539Suppl 3): 16–25.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Loscher W . Valproate enhances GABA turnover in the substantia nigra. Brain Res 1989; 501: 198–203.
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.
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.
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.
Ahluwalia P, Grewaal DS, Singhal RL . Brain GABAergic and dopaminergic systems following lithium treatment and withdrawal. Prog Neuropsychopharmacol 1981; 5: 527–530.
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.
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.
Maggi A, Enna SJ . Regional alterations in rat brain neurotransmitter systems following chronic lithium treatment. J Neurochem 1980; 34: 888–892.
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.
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.
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.
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.
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.
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.
Macdonald RL, Bergey GK . Valproic acid augments GABA-mediated postsynaptic inhibition in cultured mammalian neurons. Brain Res 1979; 170: 558–562.
Loscher W . Effect of inhibitors of GABA transaminase on the synthesis, binding, uptake, and metabolism of GABA. J Neurochem 1980; 34: 1603–1608.
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.
Loscher W, Schmidt D . Increase of human plasma GABA by sodium valproate. Epilepsia 1980; 21: 611–615.
Loscher W, Schmidt D . Plasma GABA levels in neurological patients under treatment with valproic acid. Life Sci 1981; 28: 283–288.
Shiah IS, Yatham LN, Baker GB . Divalproex sodium increases plasma GABA levels in healthy volunteers. Int Clin Psychopharmacol 2000; 15: 221–225.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Barbaccia ML, Ravizza L, Costa E . Maprotiline. An antidepressant with an unusual pharmacological profile. J Pharmacol Exp Ther 1986; 236: 307–312.
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.
Pilc A, Lloyd KG . Chronic antidepressants and GABA receptors: a GABA hypothesis of antidepressant drug action. Life Sci 1984; 35: 2149–2254.
Kimber JR,, Cross JA, Horton RW . Benzodiazepine and GABAA receptors in rat brain following chronic antidepressant drug administration. Biochem Pharmacol 1987; 36: 4173–4175.
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.
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.
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.
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.
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.
Cross JA, Horton RW . Are increases in GABAB receptors consistent findings following chronic antidepressant administration? Eur J Pharmacol 1987; 141: 159–162.
McManus DJ, Greenshaw AJ . Differential effects of antidepressants on GABAB and beta-adrenergic receptors in rat cerebral cortex. Biochem Pharmacol 1991; 42: 1525–1528.
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.
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.
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.
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.
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.
McManus DJ, Greenshaw AJ . Differential effects of chronic antidepressants in behavioural tests of beta-adrenergic and GABAB receptor function. Psychopharmacology 1991; 103: 204–208.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Griffin LD, Mellon SH . Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA. 1999; 96: 13512–13517.
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.
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.
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.
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.
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.
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.
Lavoie AM, Twyman RE . Direct evidence for diazepam modulation of GABAA receptor microscopic affinity. Neuropharmacology 1996; 35: 1383–1392.
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.
Loscher W, Schmidt D . Diazepam increases gamma-aminobutyric acid in human cerebrospinal fluid. J Neurochem 1987; 49: 152–157.
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.
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.
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.
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.
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.
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.
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.
Rush AJ, Schlesser MA, Erman M, Fairchild C . Alprazolam in bipolar-I depressions. Pharmacotherapy 1984; 4: 40–42.
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.
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.
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.
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.
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.
Brambilla, Barale F, Soares JC . Atypical antipsychotics and mood stabilization in bipolar disorder. Psychopharmacology 2003; 166: 315–332.
Fink M . Convulsive therapy: a review of the first 55 years. J Affect Disord 2001; 63: 1–15.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Petty F, Trivedi MH, Fulton M, Rush AJ . Benzodiazepines as antidepressants: does GABA play a role in depression? Biol Psychiatry 1995; 38: 578–591.
Blum BP, Mann JJ . The GABAergic system in schizophrenia. Int J Neuropsychopharmacol 2002; 5: 159–179.
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.
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.
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 (firstname.lastname@example.org) for great help with the figure.
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). https://doi.org/10.1038/sj.mp.4001362
This article is cited by
Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future
The effect and safety of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials
European Journal of Nutrition (2023)
Roundup and glyphosate’s impact on GABA to elicit extended proconvulsant behavior in Caenorhabditis elegans
Scientific Reports (2022)
Susceptibility to chronic immobilization stress‐induced depressive-like behaviour in middle‐aged female mice and accompanying changes in dopamine D1 and GABAA receptors in related brain regions
Behavioral and Brain Functions (2021)
Lithium causes differential effects on postsynaptic stability in normal and denervated neuromuscular synapses
Scientific Reports (2021)