Skip to main content
SpringerLink
Log in

New perspectives on the molecular pharmacology of affective disorders

  • Published:
European archives of psychiatry and neurological sciences Aims and scope Submit manuscript

Summary

Research with antidepressants has emphasized the importance of a delayed deamplification of the linked serotonin (5HT)/norepinephrine (NE) receptor coupled adenylate cyclase system in brain. The basic phenomena of regulation of receptor number and function of the beta adrenoceptor linked adenylate cyclase system in brain are well established, with NE regulating beta adrenoceptors in the high agonist affinity conformation (linked to adenylate cyclase and down-regulated by antidepressants), and with 5HT regulating those receptors in the low agonist affinity conformation. The biochemical effector systems of NE and 5HT are discussed and it is concluded that the final common pathway of signal transduction is protein kinase mediated phosphorylation of cellular proteins. Glucocorticoid receptors are located in the perikarya of aminergic cell bodies and may exert their effects by modifying the genomic expression of the diffusely projecting stress-responsive monoamine systems. The molecular neurobiology of beta adrenoceptors, with its implication for genetic and immunologic investigations, is briefly discussed and further research on stimulus-transcription coupling and regulation of gene expression in brain is suggested as an exciting new direction in central receptor research relevant to the psychopharmacology of affective and other disorders.

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

  • Barka T, Gubits RM, Noen HM van der (1986) Beta adrenergic stimulation of cfos gene expression in the mouse submandibular gland. Mol Cell Biol 6:2984–2989

    Google Scholar 

  • Benovic JL, Strasser RH, Caron MG, Lefkowitz RJ (1986) Beta adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor. Proc Natl Acad Sci USA 83:2797–2801

    Google Scholar 

  • Berridge MJ, Heslop JP (1981) Separate 5-hydroxytryptamine receptors on the salivary gland of the blowfly are linked to generation of either cyclic adenosine 3'5'-monophosphate or calcium signals. Br J Pharmacol 73:729–738

    Google Scholar 

  • Berridge MJ, Downes PC, Hanley MR (1982) Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 206:587–595

    Google Scholar 

  • Branton WD, Mayer E, Brownell P, Simon S (1978) Evidence for local hormonal communication between neurons in Aplysia. Nature 274:70–72

    Google Scholar 

  • Brunello N, Barbaccia ML, Chuang DM, Costa E (1982) Down-regulation of beta-adrenergic receptors following repeated injections of desmethylimipramine: permissive role of serotonergic axons. Neuropharmacology 21:1145–1149

    Google Scholar 

  • Brunello N, Volterra A, Cagiano R, Ianieri GC, Cuomo V, Racagni G (1985) Biochemical and behavioral changes in rats after prolonged treatment with desipramine: interaction with p-chlorophenylalanine. Naunyn-Schmiedeberg's Arch Pharmacol 331:20–22

    Google Scholar 

  • Brunello N, Riva M, Volterra A, Racagni G (1986) Biochemical changes in rat brain after acute and chronic administration of fluvoxamine, a selective 5HT uptake blocker: comparison with desmethylimipramine. Adv Pharmacother 2:189–196

    Google Scholar 

  • Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Groser BI, Wamsley JK (1988) Decreased beta-adrenergic receptors in rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine. Psychopharmacology 94:141–143

    Google Scholar 

  • Conn PJ, Sanders-Bush E (1985) Serotonin stimulated phosphoinositide turnover: mediation by the SZ binding site in rat cerebral cortex but not in subcortical regions. J Pharmacol Exp Ther 234:195–208

    Google Scholar 

  • Conn PJ, Sanders-Bush E (1986) Regulation of serotonin stimulated phosphoinositide hydrolysis: relation to the serotonin 5HT2 binding site. J Neurosci 6:3669–3675

    Google Scholar 

  • Conn PJ, Sanders-Bush E, Hoffman BJ, Hartig PR (1986) A unique serotonin receptor in choroid plexus is linked to phosphoinositide hydrolysis. Proc Natl Acad Sci USA 83:4086–4088

    Google Scholar 

  • Coppen A, Wood K (1982) 5-Hydroxytryptamine in the pathogenesis of affective disorders. Adv Biochem Psychopharmacol 34:249–258

    Google Scholar 

  • Curran T, Miller AD, Zokas L, Varma IM (1984) Viral and cellular fos proteins: a comparative analysis. Cell 36:259–268

    Google Scholar 

  • Dahlstrom A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 62 [Suppl 232]:1–55

    Google Scholar 

  • DaPrada M, Kettler R, Burkard W (1988) Neurochemical profile of the antidepressant moclobemide, a reversible type MAO inhibitor with minimal tyramine potentiating activity. In: Lerer B, Gershon S (eds) New directions in affective disorders. Springer, Berlin Heidelberg New York (in press)

    Google Scholar 

  • Dixon RAF, Kobilka BK, Strader BJ, Benovic JL, Dohlman HG, Mumford RA, Slater EE, Sigal IS, Caron MG, Lefkowitz RJ, Strader CO (1986) Cloning of the gene and cDNA for mammalian beta adrenergic receptor and homology with rhodopsin. Nature 321:75–79

    Google Scholar 

  • Dixon RAF, Sigal IS, Rands E, Register RB, Candelore MK, Blake AD, Strader CD (1987) Ligand binding to the beta adrenergic receptor involves its rhodopsin-like core. Nature 326:73–79

    Google Scholar 

  • Duman RS, Strada SJ, Enna SJ (1985) Effect of imipramine and adrenocorticotropin administration on the rat brain norepinephrine-coupled cyclic nucleotide generating system: alterations in alpha and beta adrenergic components. J Pharmacol Exp Ther 234:409–414

    Google Scholar 

  • Dumbrille-Ross A, Tang SW (1983) Noradrenergic and serotonergic input necessary for imipramine induced changes in beta but not S2 receptor densities. Psychiatry Res 9:207–215

    Google Scholar 

  • Enna SJ, Karbon EW (1987) Receptor regulation: evidence for a relationship between phospholipid metabolism and neurotransmitter receptor-mediated cAMP formation in brain. TIPS 8:21–24

    Google Scholar 

  • Gandolfi O, Barbaccia ML, Chuang DM, Costa E (1983) Daily bupropion injections for 3 weeks attenuate the NE-stimulation of adenylate cyclase and the number of beta adrenergic recognition sites in rat frontal cortex. Neuropharmacology 22:927–929

    Google Scholar 

  • Gilman AG (1984) G Proteins and dual control of adenylate cyclase. Cell 36:577–579

    Google Scholar 

  • Gillespie DD, Manier DH, Sanders-Bush E, Sulser F (1988) The serotonin norepinephrine link in brain. II. The role of serotonin in the regulation of beta adrenoceptors in the low agonist affinity conformation. J Pharmacol Exp Ther 244:154–159

    Google Scholar 

  • Harden TK (1983) Agonist-induced desensitization of the beta adrenergic receptor-linked adenylate cyclase. Pharmacol Rev 35:5–23

    Google Scholar 

  • Harfstrand A, Fuxe K, Cintra A, Agnati LF, Zim I, Wirkstrom AC, Okret S, Yu ZL, Goldstein M, Steinbusch H, Verhofstadt A, Gustafsson JA (1986) Demonstration of glucocorticoid receptor immunoreactivity in monoamine neurons of the rat brain. Proc Natl Acad Sci USA 83:9779–9873

    Google Scholar 

  • Harrelson AL, Rosterre W, McEwen BS (1987) Adrenocortical steroids modify neurotransmitter stimulated cyclic AMP accumulation in the hippocampus and limbic brain of the rat. J Neurochem 48:1648–1655

    Google Scholar 

  • Hunter T, Ling N, Cooper JA (1985) Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane. Nature 311:480–483

    Google Scholar 

  • Janowsky A, Okada F, Manier D, Applegate CD, Sulser F (1982) Role of serotonergic input in the regulation of the beta adrenergic receptor coupled adenylate cyclase system. Science 218:900–901

    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 

  • Kent RS, DeLean A, Lefkowitz RJ (1980) A quantitative analysis of beta adrenergic receptor interactions: resolution of high and low affinity states of the receptor by ligand binding data. Mol Pharmacol 17:14–23

    Google Scholar 

  • Kobilka BK, Dixon RAF, Frielle TH, Dohlman HG, Bolanowski MA, Sigal IS, Yang-Feng TL, Francke U, Caron MC, Lefkowitz RL (1987) cDNA for the human beta2 adrenergic receptors: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci USA 84:46–50

    Google Scholar 

  • Koe BK, Weissman A, Welch WM, Browne RG (1983) Sertraline, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther 226:686–699

    Google Scholar 

  • Kuhn R (1957) Über die Behandlung depressiver Zustände mit einem Iminodibenzyl-Derivat (G22355) Schweiz Med Wochenschr 87:1135–1140

    Google Scholar 

  • Lin CR, Chen WS, Lazar CS, Carpenter CD, Gill GN, Evans RM, Rosenfeld MG (1986) Protein kinase C phosphorylation at the Thr654 of the unoccupied EGF receptor and EGF binding regulate functional receptor loss by independent mechanisms. Cell 44:839–848

    Google Scholar 

  • Maniatis T, Goodbourn S, Fischer JA (1987) Regulation of inducible and tissue-specific gene expression. Science 236:1237–1244

    Google Scholar 

  • Manier DH, Gillespie DD, Steranka LR, Sulser F (1984) A pivotal role for serotonin in the down-regulation of beta adrenoceptors by antidepressants: reversibility of the action of p-chlorophenylalanine (PCPA) by 5-hydroxytryptophan. Experientia 40:1223–1226

    Google Scholar 

  • Manier DH, Gillespie DD, Sanders-Bush E, Sulser F (1987a) The serotonin/noradrenaline link in brain. I. The role of noradrenaline and serotonin in the regulation of density and function of beta adrenoceptors and its alteration by desipramine. Naunyn-Schmiedeberg's Arch Pharmacol 335:109–114

    Google Scholar 

  • Manier DH, Gillespie DD, Sulser F (1987b) 5,7-Dihydroxytryptamine induced lesions of serotonergic neurons and desipramine induced down-regulation of cortical beta adrenoceptors: a re-evaluation. Biochem Pharmacol 36:3308–3310

    Google Scholar 

  • Mendlewicz J, Youdim MHB (1980) Antidepressant potentiation of 5-hydroxytryptophan by 1-deprenyl in affective illness. J Affective Disord 2:137–146

    Google Scholar 

  • Mobley PL, Sulser F (1980) Adrenal corticoids regulate sensitivity of noradrenaline receptor coupled adenylate cyclase in brain. Nature 286:608–609

    Google Scholar 

  • Mobley PL, Manier DH, Sulser F (1983) Norepinephrine-sensitive adenylate cyclase system in rat brain: role of adrenal corticosteroids. J Pharmacol Exp Ther 226:71–77

    Google Scholar 

  • Morgan JI, Cohen DR, Hempstead JL, Curran T (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237:192–197

    Google Scholar 

  • Nestler EJ, Greengard P (1983) Protein phosphorylation in brain. Nature 305:583–588

    Google Scholar 

  • Nestler EJ, Walaas ST, Greengard P (1984) Neuronal phosphoproteins: physiological and clinical implications. Science 225:1357–1364

    Google Scholar 

  • Nimgoankar VL, Goodwin GM, Davies CL, Green AR (1985) Down-regulation of beta-adrenoceptors in rat cortex by repeated administration of desipramine, electroconvulsive shock and clenbuterol requires 5HT neurones but not 5HT. Neuropharmacology 24:279–283

    Google Scholar 

  • O'Donnell JM, Frazer A (1985) Effects of clenbuterol and antidepressant drugs on beta adrenergic receptor/N-protein coupling in the cerebral cortex of the rat. J Pharmacol Exp Ther 234:30–36

    Google Scholar 

  • Okada F, Tokumitsu Y, Ui M (1986) Desensitization of beta adrenergic receptor coupled adenylate cyclase in cerebral cortex after treatment in vivo of rats with desipramine. J Neurochem 47:454–459

    Google Scholar 

  • Perumal AS, Smith TM, Suckow RF, Cooper TB (1986) Downregulation of beta receptors by bupropion and its major metabolite in mouse brain. Neuropharmacology 25:1323–1326

    Google Scholar 

  • Pickel VM, Joh TH, Field PM, Becker CG, Reis DJ (1975) Cellular localization of tyrosine hydroxylase by immunohistochemistry. J Histochem Cytochem 23:1–12

    Google Scholar 

  • Piomelli D, Volterra A, Dale N, Sirgelbaum SA, Kandel ER, Schwartz JH, Belardettki F (1987) Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature 328:38–43

    Google Scholar 

  • Ringold GM (1985) Steroid hormone regulation of gene expression. Annu Rev Pharmacol Toxicol 25:529–566

    Google Scholar 

  • Roberts VJ, Singhal RL, Roberts DCS (1984) Corticosterone prevents the increase in noradrenaline stimulated adenyl cyclase activity in rat hippocampus following adrenalectomy or metopirone. Eur J Pharmacol 103:235–240

    Google Scholar 

  • Sambucetti LC, Curran T (1986) The fos protein complex is associated with DNA in isolated nuclei and binds to DNA cellulose. Science 234:1400–1419

    Google Scholar 

  • Scatton B, Lloyd KG, Zivkovic B, Dennis T, Claustre Y, Dedek J, Arbilla S, Langer SZ, Bartholini G (1987) Fengabine, a novel antidepressant GABA-ergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABA-ergic transmission in the rat. J Pharmacol Exp Ther 241:251–257

    Google Scholar 

  • Scheller RH, Jackson JF, McAllister LB, Rothman BS, Mayers E, Axel R (1983) A single gene encodes multiple neuropeptides mediating a stereotyped behavior. Cell 32:7–22

    Google Scholar 

  • Schmidt BH, Schultz JE (1986) The potential antidepressant tiflucarbine down-regulates beta adrenoceptors in rat brain. Eur J Pharmacol 130:27–35

    Google Scholar 

  • Schofield PR, Darlison MG, Fujita N, Burt DR, Stephenson FN, Rodriquez H, Rhee LM, Ramachandran J, Peale V, Glencorse TA, Seeburg PH, Barnard EA (1987) Sequence and functional expression of the GABA receptor shows a ligand-gated receptor super-family. Nature 328:221–227

    Google Scholar 

  • Schultz JE, Schmidt BH (1986) Rolipram, a stereospecific inhibitor of calmodulin independent phosphodiesterase, causes beta adrenoceptor subsensitivity in rat cerebral cortex. Naunyn-Schmiedeberg's Arch Pharmacol 333:23–30

    Google Scholar 

  • Shopsin B, Friedman E, Gershon S (1975) The use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacol Commun 1:239–249

    Google Scholar 

  • Shopsin B, Friedman E, Gershon S (1976) Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients. Arch Gen Psychiatry 33:811–819

    Google Scholar 

  • Sibley DR, Benovic JR, Caron MG, Lefkowitz RJ (1987) Regulation of transmembrane signaling by receptor phosphorylation. Cell 48:913–922

    Google Scholar 

  • Stone EA, Platt JE, Herrera AS (1986) Effect of repeated restraint stress, desmethylimipramine or adrenocorticotyropin on the alpha and beta adrenergic components of the cyclic AMP response to norepinephrine in rat brain slices. J Pharmacol Exp Ther 237:702–707

    Google Scholar 

  • Sulser F (1987) Serotonin-norepinephrine interactions in the brain: implications for the pharmacology and pathophysiology of affective disorders. J Clin Psychiatry 48:12–18

    Google Scholar 

  • Sulser F, Mishra R (1983) The discovery of tricyclic antidepressants and their mode of action. In: Parnhan MJ, Boninvels J (eds) Discoveries in pharmacology, vol 1. Elsevier, North Holland, Amsterdam, pp 233–247

    Google Scholar 

  • Sulser F, Sanders-Bush E (1987) The serotonin-norepinephrine link hypothesis of affective disorders: receptor-receptor interaction in brain. In: Ehrlich YH, Lenox RH, Kornecki E, Berry WO (eds) Molecular basis of neuronal responsiveness. Plenum Press, New York, pp 489–502

    Google Scholar 

  • Sulser F, Conn PJ, Zawad JS, Sanders-Bush E (1986) Molecular aspects of altered transmembrane regulation of the noradrenaline signal by antidepressants. In: Schou JS, Geisler A, Norm S (eds) Alfred Benzon Symposium no 22. Drug receptors and dynamic processes in cells. Munksgaard, Copenhagen, pp 364–379

    Google Scholar 

  • Taylor CW, Merritt JE (1986) Receptor coupling to polyphosphoinositide turnover: a parallel with the adenylate cyclase system. Trends Pharmacol Sci 7:238–242

    Google Scholar 

  • Van Praag HM (1982) Serotonin precursors in the treatment of depression. Adv Biochem Psychopharmacol 34:259–286

    Google Scholar 

  • Yarden Y, Rodriquez H, Wong SKF, Brandt DR, May DC, Burnie LD, Hankins RN, Chen EY, Ramachandran J, Ullrich A, Ross EM (1986) The avian beta adrenergic receptor: primary structure and membrane topology. Proc Natl Acad Sci USA 83:6795–6799

    Google Scholar 

  • Zawad JS, Brown FC (1984) Beta-adrenergic coupled phospholipid methylation: a possible role in withdrawal from chronic ethanol. Biochem Pharmacol 33:3799–3805

    Google Scholar 

  • Zawad JS, Sulser F (1986) S-Adenosyl-l-methionine modulates phosphatidylethanolamine methyltransferase response to isoproterenol in brain. Eur J Pharmacol 124:157–160

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Pharmacology and Psychiatry, Vanderbilt University School of Medicine, 37232, Nashville, TN, USA

    Fridolin Sulser

Authors
  1. Fridolin Sulser
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Parts of this article were presented on the occasion of the inauguration ceremony of the Department of Psychiatry of the University of Mainz on April 2 and 3, 1987

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sulser, F. New perspectives on the molecular pharmacology of affective disorders. Eur Arch Psychiatr Neurol Sci 238, 231–239 (1989). https://doi.org/10.1007/BF00449803

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00449803

Key words

Search

Navigation