Skip to main content
SpringerLink
Log in

Effects of subchronic administration of antidepressants and anxiolytics on levels of the α subunits of G proteins in the rat brain

  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary

The aim of this study was to examine the effects of subchronic administration of psychoactive drugs on the a subunits of G proteins in the rat brain, and also to determine if different classes of psychoactive drugs share a common property, i.e., of altering levels of these proteins. For this purpose, we selected the psychoactive drugs desipramine and phenelzine (antidepressants), lithium (antimanic), alprazolam and buspirone (anxiolytics), and meta-chlorophenylpiperazine (anxiogenic). The levels of α subunits of G proteins (Gs, Gi1/2, Gq/11) expressed in cortical, hippocampal, and cerebellar brain regions were studied by the Western blot technique. We observed that subchronic treatment with lithium significantly decreased, and with phenelzine significantly increased levels of Gi1/2α protein in the cortex and the hippocampus. On the other hand, buspirone significantly decreased levels of Gil/2α protein only in the cerebellum. Other psychoactive drugs, however, namely desipramine, meta-chlorophenylpiperazine, and alprazolam, did not alter levels of Gs, Gi1/2, or Gq/11α proteins in any of the brain regions studied. Since other studies have shown the involvement of G proteins in the mechanism of action of psychoactive drugs, our results demonstrate that expressed protein levels of the α subunit of G proteins are not altered by all the psychoactive drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Andersen PH, Geisler A (1984) Lithium inhibition of forskolin-stimulated adenylate cyclase. Neuropsychobiology 12: 1–3

    Google Scholar 

  • Avissar S, Schreiber G, Danon A, Belmaker RH (1988) Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature 331: 440–442

    Google Scholar 

  • Avissar S, Schreiber G, Aulakh CS, Wozniak KM, Murphy DL (1990) Carbama-zepine and electroconvulsive shock attenuate beta adrenoreceptor and muscarinic cholinoreceptor coupling to G proteins in rat cortex. Eur J Pharmacol 189: 99–103

    Google Scholar 

  • Baker GB, Greenshaw AJ (1989) Effects of subchronic administration of antidepressants on receptors in central nervous system. Cell Mol Neurobiol 9: 1–44

    Google Scholar 

  • Baraban JM, Worley PF, Snyder SH (1989) Second messenger systems and psychoactive drug action: focus on phosphoinositide system and lithium. Am J Psychiatry 146: 1251–1260

    Google Scholar 

  • Birnbaumer L, Abramowitz J, Yatani A, Okabe K, Mattera R, Graf R, Sanford J, Codina J, Brown AM (1990) Roles of G proteins in coupling of receptors to ionic channels and other effector systems. Crit Rev Biochem Mol Biol 25: 225–244

    Google Scholar 

  • Bockaert J, Dumuis A, Bouhelal R, Sebben M, Cory RN (1987) Piperazine derivatives including the putative anxiolytic drugs, buspirone and ipsapirone, are agonists at 5HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons. Naunyn Schmiedebergs Arch Pharmacol 335: 588–592

    Google Scholar 

  • Bunney WE Jr, Davis JM (1965) Norepinephrine in depressive reactions: a review. Arch Gen Psychiatry 13: 483–494

    Google Scholar 

  • Callahan PM, Cunningham KA (1994) Involvement of 5HT2C receptors in mediating the discriminative stimulus properties of m-chlorophenylpiperizine (mCPP). Eur J Pharmacol 257: 27–38

    Google Scholar 

  • Casebolt T, Jope RS (1989) Subchronic lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain. Biol Psychiatry 25: 329–340

    Google Scholar 

  • Chen J, Rasenick MM (1995) Chronic treatment of C6 glioma cells with antidepressant drugs increases functional coupling between a G protein (Gs) and adenylyl cyclase. J Neurochem 64: 724–732

    Google Scholar 

  • Colin SF, Chang H-C, Mollner S, Pfeuffer T, Reed RR, Duman RS, Nestler EJ (1991) Chronic lithium regulates the expression of adenylate cyclase and Gi-protein alpha subunit in rat cerebral cortex. Proc Natl Acad Sci USA 88: 10634–10637

    Google Scholar 

  • Conn PJ, Sanders-Bush E (1987) Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5HT-2 and 5HT-1C) receptors. J Pharmacol Exp Ther 242: 552–557

    Google Scholar 

  • Coppen A (1967) The biochemistry of affective disorders. Br J Psychiatry 113:1237–1264 Dunnett CW (1980) Pairwise multiple comparisons in the homogeneous variance: unequal sample size case. J Am Stat Assoc 75: 789–795

    Google Scholar 

  • Dwivedi Y, Pandey SC, Ren X, Tueting P, Pandey GN (1994) Effect of desipramine, lithium, and adinazolam on serotonin receptor subtypes in rat brain. Soc Neurosci Abstr 20: 1161

    Google Scholar 

  • Ebstein RP, Hermoni M, Belmaker RH (1980) The effect of lithium on noradrenalineinduced cyclic AMP accumulation in rat brain: inhibition after chronic treatment and absence of supersensitivity. J Pharmacol Exp Ther 213: 161–167

    Google Scholar 

  • Eison AS, Temple DL (1986) Buspirone: review of its pharmacology and current perspective on its mechanism of action. Am J Med 80 [Suppl 3B]: 1–8

    Google Scholar 

  • Emamghoreishi M, Warsh JJ, Sibony D, Li PP (1996) Lack of effect of chronic antidepressant treatment on Gs and Giα subunit protein and mRNA levels in the rat cerebral cortex. Neuropsychopharmacol 15: 281–287

    Google Scholar 

  • Freissmuth M, Casey PJ, Gilman AG (1989) G proteins control diverse pathways of transmembrane signaling. FASEB J 3: 2125–2131

    Google Scholar 

  • Gilman AG (1984) Guanine nucleotide-binding regulatory proteins and dual control of adenylate cyclase. J Clin Invest 73: 1–4

    Google Scholar 

  • Gilman AG (1987) G proteins: transducers of receptor-generated signals. Ann Rev Biochem 56: 615–649

    Google Scholar 

  • Gobbi M, Cavanus S, Miari A, Mennini T (1991) Effect of acute and chronic administration of buspirone on serotonin and benzodiazepine receptor subtypes in the rat brain: an autoradiographic study. Neuropharmacology 30: 313–321

    Google Scholar 

  • Godfrey PP, McClue SJ, White AM, Wood AJ, Grahame-Smith DG (1989) Subacute and chronic in vivo lithium treatment inhibits agonist- and sodium fluoride-stimulated inositol phosphate production in rat cortex. J Neurochem 52: 498–506

    Google Scholar 

  • Jones DT, Masters SB, Bourne HR, Reed RR (1990) Biochemical characterization of three stimulating GTP-binding proteins. The large and small forms of Gs and olfactory-specific G-protein, Golf. J Biol Chem 265: 2671–2676

    Google Scholar 

  • Kendall DA, Nahorski SR (1985) 5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortex slices: pharmacological characterization and effects of antidepressants. J Pharmacol Exp Ther 233: 473–479

    Google Scholar 

  • Kurose H, Regan JW, Caron MG, Lefkowitz RJ (1991) Functional interaction of recombinant α2 adrenergic receptor subtypes and G proteins in reconstituted phospholipid vesicles. Biochemistry 30: 3335–3341

    Google Scholar 

  • Lesch KP, Manji HK (1992) Signal transducing G proteins and antidepressant drugs: evidence for modulation of a subunit gene expression in rat brain. Biol Psychiatry 32: 549–579

    Google Scholar 

  • Lesch KP, Aulakh CS, Tolliver TJ, Hill JL, Murphy DL (1991a) Regulation of proteins by chronic antidepressant drug treatment in rat brain: tricyclics but not clorgyline increase G0α subunits. Eur J Pharmacol Mol Pharmacol Sect 207: 361–364

    Google Scholar 

  • Lesch KP, Aulakh CS, Tolliver TJ, Hill JL, Wolozin BL, Murphy DL (1991b) Differential effects of long term lithium and carbamazepine administration on Gsα and Giα protein in rat brain. Eur J Pharmacol Mol Pharmacol Sect 207: 355–359

    Google Scholar 

  • Li PP, Tarn Y-K, Young LT, Warsh JJ (1991) Lithium decreases Gs, Gi1 and Gi2 alpha subunit mRNA levels in rat cortex. Eur J Pharmacol Mol Pharmacol Sect 206: 165–166

    Google Scholar 

  • Li PP, Young LT, Tam Y-K, Sibony D, Warsh JJ (1993) Effect of chronic lithium and carbamazepine treatment on G protein subunit expression in rat cerebral cortex. Biol Psychiatry 34: 162–170

    Google Scholar 

  • Lowry OH, Roseburg NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275

    Google Scholar 

  • Manji HK (1992) G proteins: implications for psychiatry. Am J Psychiatry 149: 746–760

    Google Scholar 

  • Moriarty TM, Padrell E, Carty DJ (1990) G0 protein as signal transducer in the pertussis toxin-sensitive phosphatidylinositol pathway. Nature 343: 79–82

    Google Scholar 

  • Mork A (1990) Actions of lithium on second messenger activity in the brain. The adenylate cyclase and phosphoinositide systems. Lithium 1: 131–147

    Google Scholar 

  • Mork A, Geisler A (1989a) Effects of GTP on hormone-stimulated adenylate cyclase activity in cerebral cortex, striatum and hippocampus from rats treated chronically with lithium. Biol Psychiatry 26: 279–288

    Google Scholar 

  • Mork A, Geisler A (1989b) Effects of lithium ex vivo on the GTP-mediated inhibition of calcium-stimulated adenylate cyclase activity in rat brain. Eur J Pharmacol 168: 347–354

    Google Scholar 

  • Neer EJ (1995) Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80: 249–257

    Google Scholar 

  • Newman ME (1991) Lithium and phosphoinositide hydrolysis second messenger system: a critical review of its therapeutic relevance. Lithium 2: 187–194

    Google Scholar 

  • Newman ME, Lerer B (1988) Post-receptor-mediated increases in adenylate cyclase activity after chronic antidepressant treatment: relationship to receptor desensitization. Eur J Pharmacol 162: 345–352

    Google Scholar 

  • Newman ME, Shapira B, Lerer B (1991) Effects of lithium and desipramine on second messenger responses in rat hippocampus: relation to G protein effects. Neuropharmacology 30: 1297–1301

    Google Scholar 

  • Okada F, Tokumitsu Y, Ui M (1988) Possible involvement of pertussis toxin substrates (Gi, Go) in desipramine-induced refractoriness of adenylate cyclase in cerebral cortices of rats. J Neurochem 51: 194–199

    Google Scholar 

  • Okada F, Tokumitsu Y, Nomura Y (1989) Pertussis toxin attenuates 5-hydroxy-tryptamine1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. J Neurochem 52: 1566–1569

    Google Scholar 

  • Osborne NN (1988) Tricyclic antidepressants mianserin and ouabain stimulate inositol phosphate formation in vitro in rat cortical slices. Neurochem Res 13: 105–111

    Google Scholar 

  • Ozawa H, Rasenick MM (1991) Chronic electroconvulsive treatment augments coupling of the GTP-binding protein Gs to the catalytic moiety of adenylyl cyclase in a manner similar to that seen with chronic antidepressant drugs. J Neurochem 56: 330–338

    Google Scholar 

  • Pandey GN, Brown B, Davis JM (1985) Effect of treatment with some atypical antidepressants on [3H]-DHA binding in rat brain. Drug Dev Res 5: 251–259

    Google Scholar 

  • Pandey SC, Dwivedi Y, Pandey GN (1993) Effect of treatment with mCPP and alprazolam on serotonin receptor subtypes and phosphoinositide signaling system. 32nd Annual Meeting of the American College of Neuropharmacology, p 167 (Abstract)

  • Peroutka SJ (1985) Selective interactions of novel anxiolytics with 5-hydroxytryptamine1A receptors. Biol Psychiatry 20: 971–979

    Google Scholar 

  • Peroutka SJ, Snyder SH (1980) Chronic antidepressant treatment lowers spiorperidollabeled serotonin receptor binding. Science 210: 88–90

    Google Scholar 

  • Robinson DS, Campbell IC, Walker M, Statham NJ, Lovenberg W, Murphy DL (1979) Effect of chronic monoamine oxidase inhibitor treatment on biogenic amine metabolism in rat brain. Neuropharmacology 18: 771–776

    Google Scholar 

  • Robishaw JD, Smigel MD, Gilman AG (1986) Molecular basis for two forms of the G protein that stimulates adenylate cyclase. J Biol Chem 261: 9587–9590

    Google Scholar 

  • Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122: 509–522

    Google Scholar 

  • Schultz J (1976) Psychoactive drug effects on a system which generates cyclic AMP in brain. Nature 261: 417–418

    Google Scholar 

  • Sethy VH, Hodges DN (1982) Role of β-adrenergic receptors in the antidepressant activity of alprazolam. Res Commun Chem Pathol Pharmacol 36: 329–332

    Google Scholar 

  • Simon MI, Strathman MP, Gautam N (1991) Discovery of G proteins in signal transduction. Science 252: 802–808

    Google Scholar 

  • Song L, Jope RS (1992) Chronic lithium treatment impairs phosphatidylinositol hydrolysis in membranes from rat brain regions. J Neurochem 58: 2200–2206

    Google Scholar 

  • Spigel AM, Simonds WF, Jones TL, Goldsmith PK, Unson CG (1990) Antibodies against synthetic peptides as probes of G protein structure and function. Soc Gen Physio Ser 45: 185–195

    Google Scholar 

  • Strathmann M, Simon MI (1990) G protein diversity: a distinct class of alpha subunit is present in vertebrates and invertebrates. Proc Natl Acad Sci USA 87: 9113–9117

    Google Scholar 

  • Sulser F (1979) New perspectives on the mode of action of antidepressant drugs. Trends Pharmacol Sci 1: 92–94

    Google Scholar 

  • Sulser F (1984) Antidepressant treatments and regulation of norepinephrine-receptor-coupled adenylate cyclase systems in brain. Adv Biochem Psychopharmacol 39: 249–261

    Google Scholar 

  • Tamir J, Fawzi AB, Tamir A, Evans T, Northrup JK (1991) G proteins βγ forms: identity of β and diversity of γ subunits. Biochemistry 30: 3919–3926

    Google Scholar 

  • Todd KG, McManus DJ, Baker GB (1995) Chronic administration of the antidepressants phenelzine, desipramine, clomipramine, or maprotiline decrease binding to 5-hydroxytryptamme2A receptors without affecting benzodiazepine binding sites in rat brain. Cell Mol Neurobiol 15: 361–370

    Google Scholar 

  • Ulrichsen J, Partilla JS, Dax EM (1992) Long-term administration of mchlorophenylpiperazine (mCPP) to rats induces changes in serotonin receptor binding, dopamine levels and locomotor activity without altering prolactin and corticosterone secretion. Psychopharmacology 107: 229–235

    Google Scholar 

  • Vetulani J (1991) The development of our understanding of the mechanism of action of antidepressant drugs. Pol J Pharmacol Pharm 43: 323–338

    Google Scholar 

  • Vetulani J, Stawarz RJ, Dingel JV, Sulser F (1976) A possible common mechanism of action of antidepressant treatments. Naunyn Schmiedebergs Arch Pharmacol 293: 109–114

    Google Scholar 

  • Yamaoka K, Nanba T, Nomura S (1988) Direct influence of antidepressants on GTP binding protein of adenylate cyclase in cell membranes of the cerebral cortex of rats. J Neural Transm 71: 165–175

    Google Scholar 

  • Young LT, Li PP, Kish SJ, Siu KP, Kamble A, Hornykiewicz O, Warsh JJ (1993) Cerebral cortex Gsα protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem 61: 890–895

    Google Scholar 

Download references

Author information

Author notes

  1. G. N. Pandey

    Present address: The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

Authors and Affiliations

  1. The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Y. Dwivedi

Authors
  1. Y. Dwivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. N. Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dwivedi, Y., Pandey, G.N. Effects of subchronic administration of antidepressants and anxiolytics on levels of the α subunits of G proteins in the rat brain. J. Neural Transmission 104, 747–760 (1997). https://doi.org/10.1007/BF01291891

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01291891

Keywords

Search

Navigation