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Central GABAergic Systems and Depressive Illness

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Abstract

Clinical depression and other mood disorders are relatively common mental illnesses but therapy for a substantial number of patients is unsatisfactory. For many years clinicians and neuroscientists believed that the evidence pointed toward alterations in brain monoamine function as the underlying cause of depression. This point of view is still valid. Indeed, much of current drug therapy appears to be targeted at central monoamine function. Other results, though, indicate that GABAergic mechanisms also might play a role in depression. Such indications stem from both direct and indirect evidence. Direct evidence has been gathered in the clinic from brain scans or postmortem brain samples, and cerebrospinal fluid (CSF) and serum analysis in depressed patients. Indirect evidence comes from interaction of antidepressant drugs with GABAergic system as assessed by in vivo and in vitro studies in animals. Most of the data from direct and indirect studies are consistent with GABA involvement in depression.

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REFERENCES

  1. Schildkraut, J. J. 1965. The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am. J. Psychiatry 122:509–522.

    Google Scholar 

  2. Duman, R. S. 1999. The neurochemistry of mood disorders: Preclinical studies. Pages 333-347, in Charney D. S., Nesler, E. J., and Bunney B. S. (eds.), Neurobiology of Mental Illness. Oxford University Press, New York, NY.

    Google Scholar 

  3. Garlow, S. J. 1999. The neurochemistry of mood disorders: Clinical studies. Pages 348-364, in CharneyD. S., Nesler, E. J. and BunneyB. S. (eds.), Neurobiology of Mental Illness. Oxford University Press, New York, NY.

    Google Scholar 

  4. Krnjevic, K. 1991. Significance of GABA in brain. Pages 47-87, in Tunnicliff, G. and Raess, B. U. (eds.), GABA Mechanisms Epilepsy. Wiley-Liss, New York, NY.

    Google Scholar 

  5. Paul, S. M. 1995. GABA and glycine. Pages 87-94, in Bloom, F. and Kupfer, D. (eds.), Psychopharmacology, the Fourth Generation of Progress. Raven Press, New York, NY.

    Google Scholar 

  6. Onteniente, B., Simon, H., Taghzouti, K., Geffard, M., Le Moal, M, and Calas, A. 1987. Dopamine-GABA interactions in the nucleus accumbens and lateral septum of the rat. Brain Res. 421:391–396.

    Google Scholar 

  7. Login, I. S., Pal, S. N., Adams, D. T., and Gold, P. E. 1998. Muscimol increases acetylcholine release by directly stimulating adult striatal cholinergic interneurons. Brain Res 779:33–40.

    Google Scholar 

  8. Van den Pol, A. N. and Obrietan, K. 2000. Neuromodulation of GABA in developing and mature hypothalamic neurons. Pages 409-438, in Martin, D. L. and Olsen, R. W. (eds.), GABA in the Nervous System: The View at Fifty Years. Lippcnott, Williams and Wilkins, Philadelphia, PA.

    Google Scholar 

  9. American Psychiatric and Association 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association, Washington, D. C.

  10. Robins, L. N., Helzer, J. E., and Weissman, M. M. 1987. Lifetime prevalance of specific psychiatric disorders in three sites. Arch. Gen. Psychiat. 44:152–156.

    Google Scholar 

  11. Black, D. W., Wanock, C., and Winokur, G. 1976. The Iowa linkage study I: Suicide and accidental deaths among psychiatric patients. Arch. Gen. Psychiat. 33:1029–1037.

    Google Scholar 

  12. Muller-Oerlinghausen, B., Muser-Causemann, B., and Volk, J. 1992. Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. J. Affect. Disord. 25:261–269.

    Google Scholar 

  13. Kovacs, M., Goldston, D., and Gatsonis, C. 1993. Suicidal behaviors and childhood-onset depressive disorders: A longitudinal investigation. J. Am. Acad. Child. Adolesc. Psychiatry 32:8–20.

    Google Scholar 

  14. Ahrens, B., Muller-Oerlinghausen, B., Schou, M., Wolf, T., Alda, M., Grof, E., Grof, P., Lenz, G., Simhandl, C., Thau, K. et al. 1995. Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium pophylaxis. J. Affect. Disord. 33:67–75.

    Google Scholar 

  15. Dilsaver, S. C., Chen, Y. W., Swann, A. C., Shoaib, A. M., and Krajewski, K. J. 1994. Suicidality in patients with pure and depressive mania. Am. J. Psychiatry 151:1312–1315.

    Google Scholar 

  16. Weeke, A., Jule, K. and Veath, M. 1987. Cardiovascular death and manic depressive psychosis. J. Affect. Disord. 13:287–292.

    Google Scholar 

  17. Dilsaver, S. C. and Coffman, J. 1988. Depression and hypertension. Psychiatr. Res. 26:115–117.

    Google Scholar 

  18. Moldin, S. O., Reich, T., and Rice, J. P. 1991. Current perspectives on the genetics of unipolar depression. Behav. Genet. 21:211–242.

    Google Scholar 

  19. Nurnberger, J. I. and Berrettini, W. 2000. Psychiatric genetics. Pages 61-71, in Ebert, M. H., Loosen, P. T., and Nurcombe, B. (eds), Current Diagnostics in Psychiatry. Lange Medical Books/McGraw Hill, New York, NY.

    Google Scholar 

  20. Nurnberger, J. I. and Foroud, T. 2000. Genetics of bipolar affective disorder. Curr. Psychiatry Rep. 2:147–157.

    Google Scholar 

  21. Serretti, A., Macciardi, F., Cusin, C., Lattuada, E., Lilli, R., Di Bella, D., Catalano, M., and Smeraldi, E. 1998. GABAA alpha-1 subunit gene not associated with depressive symptomatology in mood disorders. Psychiatr. Genet. 8:251–254.

    Google Scholar 

  22. Papadimitriou, G. N., Dikeos, D. G., Karadima, G., Avramopoulos, D., Daskalopoulou, E. G., Vassilopoulos, D., and Stefanis, C. N. 1998. Association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) and bipolar affective disorder. Am. J. Med. Genet. 81:73–80.

    Google Scholar 

  23. Papadimitriou, G. N., Dikeos, D. G., Karadima, G., Avramopoulos, D., Daskalopoulou, E. G., and Stefanis, C. N. 2001. GABA-A receptor beta3 and alpha5 subunit gene cluster on chromosome 15q11-q13 and bipolar disorder: A genetic association study. Am. J. Med. Genet. 105:317–320.

    Google Scholar 

  24. Tunnicliff, G. and Ngo, T. T. 1986. Regulation of γ-aminobutyric acid synthesis in the vertebrate nervous system. Neurochem. Int. 8:287–297.

    Google Scholar 

  25. Enna, S. J. and Bowery, N. J. 1997. The GABA Receptors. Humana Press, Towawa, NJ.

    Google Scholar 

  26. Krnjevic, K. and Schwartz, S. 1967. The action of gamma-aminobutyric acid on cortical neurones. Exp. Brain Res. 3:320–336.

    Google Scholar 

  27. Cherubini, E. and Strata, F. 1997. GABAC receptors: A novel receptor family with unusual pharmacology. News Physiol. Sci. 12:136–141.

    Google Scholar 

  28. Sodickson, D. L. and Bean, B. P. 1996. GABAB receptor-activated inwardly rectifying potassium current in dissociated hippocampal CA3 neurons. J. Neurosci. 16:6374–6385.

    Google Scholar 

  29. Ng, G. Y., Clark, J., Coulombe, N., Ethier, N., Hebert, T. E., Sullivan, R., Kargman, S., Chateauneuf, A., Tsukamoto, N., McDonald, T., Whiting, P., Mezey, E., Johnson, M. P., Liu, Q., Kolakowski, L. F., Jr., Evans, J. F., Bonner, T. I., and O'Neill, G. P. 1999 Identification of a GABAB receptor subunit, gb2, required for functional GABAB receptor activity. J. Biol. Chem. 274:7607–7610.

    Google Scholar 

  30. Liu, Q. R., Lopez-Corcuera, B., Mandiyan, S., Nelson, H., and Nelson, N. 1993. Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain. J. Biol. Chem. 268:2106–2112.

    Google Scholar 

  31. Borden, L. A. 1996. GABA transporter heterogeneity: Pharmacology and cellular localization. Neurochem. Int. 29:335–356.

    Google Scholar 

  32. Radian, R., Bendahan, A., and Kanner, B. I. 1986. Purification and identification of the functional sodium-and chloride-coupled gamma-aminobutyric acid transport glycoprotein from rat brain. J. Biol. Chem. 261:15437–15441.

    Google Scholar 

  33. King, S. M. and Tunnicliff, G. 1990. Na+-and Cl--dependent [3H]GABA binding to catfish brain particles. Biochem. Int. 20:821–831.

    Google Scholar 

  34. Mehta, A. K. and Ticku, M. K. 1999. An update on GABAA receptors. Brain Res. Brain Res. Rev. 29:196–217.

    Google Scholar 

  35. Rabow, L. E., Russek, S. J., and Farb, D. H. 1995. From ion currents to genomic analysis: Recent advances in GABAA receptor research. Synapse 21:189–274.

    Google Scholar 

  36. Wong, G., Sei, Y., and Skolnick, P. 1992. Stable expression of type I gamma-aminobutyric acidA/benzodiazepine receptors in a transfected cell line. Mol. Pharmacol. 42:996–1003.

    Google Scholar 

  37. Valeyev, A. Y., Barker, J. L., Cruciani, R. A., Lange, G. D., Smallwood, V. V., and Mahan, L. C. 1993. Characterization of the gamma-aminobutyric acidA receptor-channel complex composed of alpha 1 beta 2 and alpha 1 beta 3 subunits from rat brain. J. Pharmacol. Exp. Ther. 265:985–991.

    Google Scholar 

  38. Hevers, W. and Luddens, H. 1998. The diversity of GABAA receptors: Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol. Neurobiol. 18:35–86.

    Google Scholar 

  39. De Blas, A. L. 1996. Brain GABAA receptors studied with subunit-specific antibodies. Mol. Neurobiol. 12:55–71.

    Google Scholar 

  40. Huntsman, M. M., Isackson, P. J., and Jones, E. G. 1994. Lamina-specific expression and activity-dependent regulation of seven GABAA receptor subunit mRNAs in monkey visual cortex. J. Neurosci. 14:2236–2259.

    Google Scholar 

  41. M cK ernan, R. M. and Whiting, P. J. 1996. Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. 19:139–143.

    Google Scholar 

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

    Google Scholar 

  43. Post, R. M., Ballenger, J. C., Hare, T. A., Goodwin, F. K., Lake, C. R., Jimerson, D. C., and Bunney, W. E. 1980. Cerebrospinal fluid GABA in normals and patients with affective disorders. Brain Res. Bull. 5:755–759.

    Google Scholar 

  44. Zimmer, R., Teelken, A. W., Meier, K. D., Ackenheil, M., and Zander, K. J. 1980. Preliminary studies on CSF gamma-aminobutyric acid levels in psychiatric patients before and during treatment with different psychotropic drugs. Prog. Neuropsychopharmacol. 4:613–620.

    Google Scholar 

  45. Roy, A., Dejong, J., and Ferraro, T. 1991. CSF GABA in depressed patients and normal controls. Psychol. Med. 21:613–618.

    Google Scholar 

  46. Gold, B. I., Bowers, M. B., Jr., Roth, R. H., and Sweeney, D. W. 1980. GABA levels in CSF of patients with psychiatric disorders. Am. J. Psychiatry 137:362–364.

    Google Scholar 

  47. Gerner, R. H. and Hare, T. A. 1981. CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am. J. Psychiatry 138:1098–1101.

    Google Scholar 

  48. Berrettini, W. H., Nurnberger, J. I., Jr., Hare, T., Gershon, E. S., and Post, R. M. 1982. Plasma and CSF GABA in affective illness. Br. J. Psychiatry 141:483–487.

    Google Scholar 

  49. Gerner, R. H., Fairbanks, L., Anderson, G. M., Young, J. G., Scheinin, M., Linnoila, M., Hare, T. A., Shaywitz, B. A., and Cohen, D. J. 1984. CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls. Am. J. Psychiatry 141:1533–1540.

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  52. Petty, F. and Sherman, A. D. 1984. Plasma GABA levels in psychiatric illness. J. Affect. Disord. 6:131–138.

    Google Scholar 

  53. Petty, F., Kramer, G. L., Gullion, C. M., and Rush, A. J. 1992. Low plasma gamma-aminobutyric acid levels in male patients with depression. Biol. Psychiatry 32:354–363.

    Google Scholar 

  54. Petty, F., Kramer, G. L., Fulton, M., Moeller, F. G., and Rush, A. J. 1993. Low plasma GABA is a trait-like marker for bipolar illness. Neuropsychopharmacology 9:125–132.

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  57. Petty, F., Fulton, M., Kramer, G. L., Kram, M., Davis, L. L., and Rush, A. J. 1999. Evidence for the segregation of a major gene for human plasma GABA levels. Mol. Psychiatry 4:587–589.

    Google Scholar 

  58. Devanand, D. P., Shapira, B., Petty, F., Kramer, G., Fitzsimons, L., Lerer, B., and Sackeim, H. A. 1995. Effects of electroconvulsive therapy on plasma GABA. Convuls. Ther. 11:3–13.

    Google Scholar 

  59. Mervaala, E., Kononen, M., Fohr, J., Husso-Saastamoinen, M., Valkonen-Korhonen, M., Kuikka, J. T., Viinamaki, H., Tammi, A. K., Tiihonen, J., Partanen, J., and Lehtonen, J. 2001. SPECT and neuropsychological performance in severe depression treated with ECT. J. Affect. Disord. 66:47–58.

    Google Scholar 

  60. Berrettini, W. H., Umberkoman-Wiita, B., Nurnberger, J. I., Jr., Vogel, W. H., Gershon, E. S., and Post, R. M. 1982. Platelet GABA-transaminase in affective illness. Psychiatry Res. 7:255–260.

    Google Scholar 

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

    Google Scholar 

  62. Korpi, E. R., Kleinman, J. E., and Wyatt, R. J. 1988. GABA concentrations in forebrain areas of suicide victims. Biol. Psychiatry 23:109–114.

    Google Scholar 

  63. Cheetham, S. C., Crompton, M. R., Katona, C. L., Parker, S. J., and Horton, R. W. 1988. Brain GABAA/benzodiazepine binding sites and glutamic acid decarboxylase activity in depressed suicide victims. Brain Res. 460:114–123.

    Google Scholar 

  64. Perry, E. K., Gibson, P. H., Blessed, G., Perry, R. H., and Tomlinson, B. E. 1977. Neurotransmitter enzyme abnormalities in senile dementia: Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J. Neurol. Sci. 34:247–265.

    Google Scholar 

  65. Honig, A., Bartlett, J. R., Bouras, N., and Bridges, P. K. 1988. Amino acid levels in depression: A preliminary investigation. J. Psychiatr. Res. 22:159–164.

    Google Scholar 

  66. Martin, D. L. and Tobin, A. J. 2000. Mechanisms controlling GABA synthesis and degradation in brain. Pages 25-41, in Martin, D. L., and Olsen, R. W. GABA in the Nervous System: The View at Fifty Years. Lippincott Williams and Wilkins, Philadelphia, PA.

    Google Scholar 

  67. Asada, H., Kawamura, Y., Maruyama, K., Kume, H., Ding, R., Ji, F. Y., Kanbara, N., Kuzume, H., Sanbo, M., Yagi, T., and Obata, K. 1996. Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65), maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures. Biochem. Biophys. Res. Commun. 229:891–895.

    Google Scholar 

  68. Asada, H., Kawamura, Y., Maruyama, K., Kume, H., Ding, R. G., Kanbara, N., Kuzume, H., Sanbo, M., Yagi, T., and Obata, K. 1997. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc. Natl. Acad. Sci. USA 94:6496–6499.

    Google Scholar 

  69. Toth, Z., Bunney, W. E., Potkin, S. G., and Jones, E. G. 1999. Gene expression for glutamic acid decarboxylase is increased in prefrontal cortex of depressed patients. Soc. Neurosci. Abs. 29:2097.

    Google Scholar 

  70. Sanacora, G., Mason, G. F., Rothman, D. L., Behar, K. L., Hyder, F., Petroff, O. A., Berman, R. M., Charney, D. S., and Krystal, J. H. 1999. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 56:1043–1047.

    Google Scholar 

  71. SanacoraG., MasonG. F., RothmanD. L., and KrystalJ. H. 2002. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am. J. Psychiatry 159:663–665.

    Google Scholar 

  72. Willner, P. 1984. The validity of animal models of depression. Psychopharmacology 83:1–16.

    Google Scholar 

  73. Willner, P. and Papp, M. 1997. Animal models to detect antidepressants. Pages 213-234, in SkolnickP. (ed.), Antidepressants: New Pharmacological Strategies Humana Press, Totowa, NJ.

    Google Scholar 

  74. Seligman, M. E. and Maier, S. F. 1967. Failure to escape traumatic shock. J. Exp. Psychol. 7:1–9.

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  77. Drugan, R. C., Maier, S. F., Skolnick, P., Paul, S. M., and Crawley, J. N. 1985. An anxiogenic benzodiazepine receptor ligand induces learned helplessness. Eur. J. Pharmacol. 113:453–458.

    Google Scholar 

  78. Stanford, S. C., Taylor, S. C., and Little, H. J. 1987. Chronic desipramine treatment prevents the upregulation of cortical beta-receptors caused by a single dose of the benzodiazepine inverse agonist FG7142. Eur. J. Pharmacol. 139:225–232.

    Google Scholar 

  79. Martin, P., Pichat, P., Massol, J., Soubrie, P., Lloyd, K. G., and Puech, A. J. 1989. Decreased GABAB receptors in helpless rats: Reversal by tricyclic antidepressants. Neuropsychobiology 22:220–224.

    Google Scholar 

  80. Jancsar, S. M. and Leonard, B. E. 1984. Changes in neurotransmitter metabolism following olfactory bulbectomy in the rat. Prog. Neuropsychopharmacol. Biol. Psychiatry 8:263–269.

    Google Scholar 

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

    Google Scholar 

  82. Lloyd, K. G., Morselli, P. L., Depoortere, H., Fournier, V., Zivkovic, B., Scatton, B., Broekkamp, C., Worms, P., and Bartholini, G. 1983. The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials. Pharmacol. Biochem Behav 18:957–966.

    Google Scholar 

  83. Porsolt, R. D., Le Pichon, M., and Jalfre, M. 1977. Depression: A new animal model sensitive to antidepressant treatment. Nature 266:730.

    Google Scholar 

  84. Willner, P. 1990. Animal models of depression: An overview. Pharmacol. Ther. 45:425–455.

    Google Scholar 

  85. Borsini, F., Evangelista, S., and Meli, A. 1986. Effect of GABAergic drugs in the behavioral ‘despair’ test in rats. Eur. J. Pharmacol. 121:26526–26528.

    Google Scholar 

  86. Nakagawa, Y., Ishima, T., Ishibashi, Y., Tsuji, M., and Takashima, T. 1996. 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. 728:225–230.

    Google Scholar 

  87. Borsini, F. and Meli, A. 1988. Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology 94:147–160.

    Google Scholar 

  88. Lambert, J. J., Belelli, D., Hill-Venning, C., Callachan, H., and Peters, J. A. 1996. Neurosteroid modulation of native and recombinant GABAA receptors. Cell Mol. Neurobiol. 16:155–174.

    Google Scholar 

  89. Lambert, J. J., Belelli, D., Hill-Venning, C., and Peters, J. A. 1995. Neurosteroids and GABAA receptor function. Trends Pharmacol. Sci. 16:295–303.

    Google Scholar 

  90. Khisti, R. T., Chopde, C. T., and Jain, S. P. 2000. Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5-alpha-pregnan-20-one in mice forced swim test. Pharmacol. Biochem. Behav. 67:137–143.

    Google Scholar 

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

    Google Scholar 

  92. Malatynska, E. and Kostowski, W. 1984. The effect of antidepressant drugs on dominance behavior in rats competing for food. Pol. J. Pharmacol. Pharm. 36:531–540.

    Google Scholar 

  93. Malatynska, E., De Leon, I., Allen, D., and Yamamura, H. I. 1995. Effects of amitriptyline on GABA-stimulated 36Cl- uptake in relation to a behavioral model of depression. Brain Res. Bull. 37:53–59.

    Google Scholar 

  94. Knapp, R. J., Goldenberg, R., Shuck, C., Cecil, A., Watkins, J., Miller, C., Crites, G., and Malatynska, E. 2002. Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur. J. Pharmacol. 440:27–35.

    Google Scholar 

  95. Malatynska, E., Goldenberg, R., Shuck, L., Haque, A., Zamecki, P., Crites, G., Schindler, N., and Knapp, R. J. 2002. Reductions of submissive behavior in rats: A test for antidepressant drug activity. Pharmacology 64:8–17.

    Google Scholar 

  96. Lloyd, K. G., Thuret, F., and Pilc, A. 1986. GABA and the mechanism of action of antidepressant drugs. L. E. R. S. 4:33–41.

    Google Scholar 

  97. Morselli, P. L., Fournier, V., Macher, J. P., Orofiamma, B., Botin, P., and Huber, P. 1986. Therapeutic action of progabide in depressive illness: A controlled clinical trial pp. 119-126 in Bartholini, G., Lloyd, K. G., and Morselli, P. L. (eds.), GABA and Mood Disorders: Experimental and Clinical Research. Raven Press, New York, NY.

    Google Scholar 

  98. Gottesfeld, Z. and Elliott, K. A. 1971. Factors that affect the binding and uptake of GABA by brain tissue. J. Neurochem. 18:683–690.

    Google Scholar 

  99. Iversen, L. L. and Johnston, G. A. 1971. GABA uptake in rat central nervous system: Comparison of uptake in slices and homogenates and the effects of some inhibitors. J. Neurochem. 18:1939–1950.

    Google Scholar 

  100. Weinstein, H., Varon, S., and Roberts, E. 1971. Effects of imipramine on the Na+-dependent exchange and retention of gamma-aminobutyric acid by mouse brain subcellular particles. Biochem. Pharmacol. 20:103–117.

    Google Scholar 

  101. Harris, M., Hopkin, J. M., and Neal, M. J. 1973. Effect of centrally acting drugs on the uptake of gamma-aminobutyric acid (GABA) by slices of rat cerebral cortex. Br. J. Pharmacol. 47:229–239.

    Google Scholar 

  102. Snodgrass, S. R., Hedley-Whyte, E. T., and Lorenzo, A. V. 1973. GABA transport by nerve ending fractions of cat brain. J. Neurochem. 20:771–782.

    Google Scholar 

  103. Olsen, R. W., Ticku, M. K., Van Ness, P. C., and Greenlee, D. 1978. Effects of drugs on gamma-aminobutyric acid receptors, uptake, release and synthesis in vitro. Brain Res. 139:277–294.

    Google Scholar 

  104. Pilc, A. and Lloyd, K. G. 1984. Chronic antidepressants and GABA “B” receptors: A GABA hypothesis of antidepressant drug action. Life Sci. 35:2149–2154.

    Google Scholar 

  105. Popov, N. and Matthies, H. 1969. Some effects of monoamine oxidase inhibitors on the metabolism of gamma-aminobutyric acid in rat brain. J. Neurochem. 16:899–907.

    Google Scholar 

  106. Patel, G. J., Schatz, R. P., Constantindies, S. M., and Lal, H. 1975. Effect of desipramine and pargyline on brain gamma-aminobutyric acid. Biochem. Pharmacol. 24:57–60.

    Google Scholar 

  107. Tunnicliff, G. 1976. Centrally-acting drugs and the formation of brain gamma-aminobutyric acid. Gen. Pharmacol. 7:259–262.

    Google Scholar 

  108. M cM anus, D. J., Baker, G. B., Martin, I. L., Greenshaw, A. J., and M cK enna, K. F. 1992. Effects of the antidepressant/antipanic drug phenelzine on GABA concentrations and GABA-transaminase activity in rat brain. Biochem. Pharmacol. 43:2486–2489.

    Google Scholar 

  109. Lloyd, K. G., Morselli, P. L., and Bartholini, G. 1987. GABA and affective disorders. Med. Biol. 65:159–165.

    Google Scholar 

  110. Suranyi-Cadotte, B. E., Dam, T. V., and Quirion, R. 1984. Antidepressant-anxiolytic interaction: Decreased density of benzodiazepine receptors in rat brain following chronic administration of antidepressants. Eur. J. Pharmacol. 106:673–675.

    Google Scholar 

  111. Suzdak, P. D. and Gianutsos, G. 1985. 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 24:217–222.

    Google Scholar 

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

    Google Scholar 

  113. Squires, R. F. and Saederup, E. 1988 Antidepressants and metabolites that block GABAA receptors coupled to 35 S-t-butylbicyclophosphorothionate binding sites in rat brain. Brain Res. 441:15–22.

    Google Scholar 

  114. Squires, R. F. and Saederup, E. 1998. Clozapine and several other antipsychotic/antidepressant drugs preferentially block the same ‘core’ fraction of GABA(A) receptors. Neurochem. Res. 23:1283–1290.

    Google Scholar 

  115. Medvedev, A. E., Shvedov, V. I., Chulkova, T. M., Fedotova, O. A., Saederup, E., and Squires, R. F. 1998. The influence of the antidepressant pirlindole and its dehydro-derivative on the activity of monoamine oxidase A and GABAA receptor binding. J. Neural. Transm. Suppl. 52:337–342.

    Google Scholar 

  116. Tunnicliff, G., Schindler, N. L., Crites, G. J., Goldenberg, R., Yochum, A., and Malatynska, E. 1999. The GABAA receptor complex as a target for fluoxetine action. Neurochem. Res. 24:1271–1276.

    Google Scholar 

  117. Malatynska, E., Serra, M., Ikeda, M., Biggio, G., and Yamamura, H. I. 1988. Modulation of GABA-stimulated chloride influx by beta-carbolines in rat brain membrane vesicles. Brain Res. 443:395–397.

    Google Scholar 

  118. Ikeda, M., Knapp, R. J., Malatynska, E., and Yamamura, H. I. 1989. Amoxapine inhibition of GABA-stimulated chloride conductance: Investigations of potential sites of activity. Life Sci. 45:1903–1910.

    Google Scholar 

  119. Malatynska, E., Crites, G., Yochum, A., Kopp, R., Giroux, M. L., and Dilsaver, S. C. 1998. Schild regression analysis of antidepressant and bicuculline antagonist effects at the GABAA receptor. Pharmacology 57:117–123.

    Google Scholar 

  120. Malatynska, E., Giroux, M. L., Dilsaver, S. C., and Schwarzkopf, S. B. 1991. Chronic treatment with amitriptyline alters the GABA-mediated uptake of 36Cl- in the rat brain. Pharmacol. Biochem. Behav. 39:553–556.

    Google Scholar 

  121. Malatynska, E., Miller, C., Schindler, N., Cecil, A., Knapp, A., Crites, G., and Rogers, H. 1999. Amitriptyline increases GABA-stimulated 36Cl- influx by recombinant (α1γ2) GABAA receptors. Brain Res. 851:277–280.

    Google Scholar 

  122. Boyer, P. A., Skolnick, P., and Fossom, L. H. 1998. Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain: A quantitative in situ hybridization study. J. Mol. Neurosci. 10:219–233.

    Google Scholar 

  123. Le Poul, E., Boni, C., Hanoun, N., Laporte, A. M., Laaris, N., Chauveau, J., Hamon, M., and Lanfumey, L. 2000. Differential adaptation of brain 5-HT1A and 5-HT1B receptors and 5-HT transporter in rats treated chronically with fluoxetine. Neuropharmacology 39:110–122.

    Google Scholar 

  124. Tanay, V. A., Glencorse, T. A., Greenshaw, A. J., Baker, G. B., and Bateson, A. N. 1996. Chronic administration of antipanic drugs alters rat brainstem GABAA receptor subunit mRNA levels. Neuropharmacology 35:1475–1482.

    Google Scholar 

  125. Tanay, V. M., Greenshaw, A. J., Baker, G. B., and Bateson, A. N. 2001. Common effects of chronically administered antipanic drugs on brainstem GABA(A) receptor subunit gene expression. Mol. Psychiatry 6:404–412.

    Google Scholar 

  126. Reynolds, J. N. and Prasad, A. 1991. Ethanol enhances GABAA receptor-activated chloride currents in chick cerebral cortical neurons. Brain Res. 564:138–142.

    Google Scholar 

  127. Proctor, W. R., Soldo, B. L., Allan, A. M., and Dunwiddie, T. V. 1992. Ethanol enhances synaptically evoked GABAA receptor-mediated responses in cerebral cortical neurons in rat brain slices. Brain Res. 595:220–227.

    Google Scholar 

  128. Carlen, P. L., Gurevich, N., Davies, M. F., Blaxter, T. J., and O'Beirne, M. 1985. Enhanced neuronal K+ conductance: A possible common mechanism for sedative-hypnotic drug action. Can. J. Physiol. Pharmacol. 63:831–837.

    Google Scholar 

  129. Gage, P. W. and Robertson, B. 1985. Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus. Br. J. Pharmacol. 85:675–681.

    Google Scholar 

  130. Mancillas, J. R., Siggins, G. R., and Bloom, F. E. 1986. Systemic ethanol: Selective enhancement of responses to acetylcholine and somatostatin in hippocampus. Science 231:161–163.

    Google Scholar 

  131. Siggins, G. R., Pittman, Q. J., and French, E. D. 1987. Effects of ethanol on CA1 and CA3 pyramidal cells in the hippocampal slice preparation: An intracellular study. Brain Res. 414:22–34.

    Google Scholar 

  132. Malatynska, E., Dilsaver, S. C., Knapp, R. J., Giroux, M. L., Ikeda, M., and Yamamura, H. I. 1991. The interaction of a benzodiazepine receptor antagonist (Ro15-1788) with GABA and GABA receptor antagonists at the GABAA receptor chloride-ionophore complex. Neurochem. Int. 18:405–410.

    Google Scholar 

  133. Schild, H. O. 1949. pA2 and competitive drug antagonism. Br. J. Pharmacol. 4:277–280.

    Google Scholar 

  134. Schild, H. O. 1957. Drug antagonism and pA2. Pharmacol. Rev. 9:242–246.

    Google Scholar 

  135. Kenakin, T. P. 1982. The Schild regression in the process of receptor classification. Can. J. Physiol. Pharmacol. 60:249–265.

    Google Scholar 

  136. Malatynska, E., Crites, G. J., Harrawood, D., Goldenberg, R., and Matheson, G. K. 2000. Antidepressant effects on GABA-stimulated 36Cl- influx in rat cerebral cortex are altered after treatment with GABAA receptor antisense oligodeoxynucleotides. Brain Res. 869:78–84.

    Google Scholar 

  137. Malatynska, E., Matheson, G. K., Goldenberg, R., Crites, G. J., Schindler, N. L., Weinzapfel, D., Harrawood, D., Yochum, A., and Tunnicliff, G. 2000. Effects of treatment with GABA(A) receptor subunit antisense oligodeoxynucleotides on GABA-stimulated 36Cl- influx in the rat cerebral cortex. Neurochem. Int. 36:45–54.

    Google Scholar 

  138. Gunther, U., Benson, J., Benke, D., Fritschy, J. M., Reyes, G., Knoflach, F., Crestani, F., Aguzzi, A., Angoni, M., and Lang, Y. 1995. Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. PNAS 92:7749–7753.

    Google Scholar 

  139. Crestani, F., Lorez, M., Baer, K., Essrich, C., Benke, D., Laurent, J. P., Belzung, C., Fritschy, J. M., Luscher, B. and Mohler, H. 1999. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nature Neurosci. 2:833–839.

    Google Scholar 

  140. Sur, C., Wafford, K. A., Reynolds, D. S., Hadingham, K. L., Bromidge, F., Macaulay, A., Collinson, N., O'Meara, G., Howell, O., Newman, R., Myers, J., Atack, J. R., Dawson, G. R., M cK ernan, R. M., Whiting, P. J., and Rosahl, T. W. 2001. Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice. J. Neurosci. 21:3409–3418.

    Google Scholar 

  141. Skolnick, P. 1997. Introduction. Pages 10-11, in Skolnick, P. (ed.), Antidepressants: New Pharmacological Strategies. Humana Press, Totowa, NJ.

    Google Scholar 

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Tunnicliff, G., Malatynska, E. Central GABAergic Systems and Depressive Illness. Neurochem Res 28, 965–976 (2003). https://doi.org/10.1023/A:1023287729363

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