Abstract
The emergence of molecular neurobiology is rapidly changing the traditional focus of antidepressant drug research with emphasis on effector sites beyond the receptors. This switch in emphasis is leading to new conceptual and methodological approaches to understanding the mode of action of antidepressants. Events beyond the receptors—intracellular signal transduction pathways and regulation of programs of gene expression—are promising new and exciting targets for antidepressants. A short historical review of the evolution of hypotheses (e.g., monoamine, b-adrenoceptor down-regulation, and the 5-HT/NE/ glucocorticoid link) concerning the mode of action of antidepressants is first presented. The chapter then presents an overview of new hypotheses concerning the mode of action of antidepressants and discusses the role of N-methyl-D-aspartate (NMDA) receptors in antidepressant action and the possible role of corticotropin releasing factor (CRF) antagonists and substance P receptor antagonists as antidepressants. Neurotransmitter-induced intracellular processes and the importance of crosstalk at the level of protein kinases are described. The chapter than discusses protein kinase C-related processes, G proteins, and transcription factors as potential targets for antidepressants and considers the convergence of neurotransmitter signals beyond the receptors at the level of protein kinase-mediated phosphorylation. To discover the next generation of antidepressants, two avenues of interrelated investigations seem promising: (1) a more rigorous elucidation of the molecular psychopathology of affective disorders and the development of animal models of depression with greater disease validity and (2) the development of new methodology to explore mechanisms beyond the receptors and second messengers in animal models of depression and in patients with affective disorders. Possible models of depression that may have increased disease validity are described. The chapter concludes with a discussion of how programs of gene expression are likely to affect antidepressant drug development. Differentially expressed genes and their protein products can be used as novel drug targets for the development of the next generation of antidepressants, which hopefully will meet the yet unmet criteria of greater efficacy, shorter onset of therapeutic action, and efficacy in therapy-resistant depression.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Ainsworth K, Smith SE, Zetterstrom TS, Pei Q, Franklin M, Sharp T (1998) Effect of anti-depressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat. Psychopharmacology (Berl) 140:470–477
American Psychiatric Association (1994) Diagnostic and statistical Manual of Mental Disorders: 4th Ed., American Psychiatric Association, Washington, D.C.
Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrich P, Karin M (1987) Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49:729–739
Antoni FA, Palkovits M, Makara GB, Linton EA, Lowry PJ, Kiss JZ (1983) Immunoreactive corticotropin-releasing hormone in the hypothalamoinfundibular tract. Neuroendocrinology 36:415–423
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12
Assie MB, Broadhurst A, Briley M (1988) Is down-regulation of b adrenoceptors necessary for antidepressant activity? In: Briley M, Fillion G (eds) New concepts in depression. MacMillan Press, London, pp 161–166
Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F (2000) Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 47:305–313
Avissar S, Schreiber G (1992a) Interaction of antibipolar and antidepressant treatments with receptor-coupled G proteins. Pharmacopsychiatry 25:44–50
Avissar S, Schreiber G (1992b) The involvement of guanine nucleotide binding proteins in the pathogenesis and treatment of affective disorders. Biol Psychiatry 31:435–459
Avissar S, Nechamkin Y, Barki-Harrington L, Roitman G, Schreiber G (1997a) Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent. J Affect Disord 43:85–93
Avissar S, Nechamkin Y, Roitman G, Schreiber G (1997b) Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression. Am J Psychiatry 154:211–217
Avissar S, Nechamkin Y, Roitman G, Schreiber G (1998) Dynamics of ECT normalization of low G protein function and immunoreactivity in mononuclear leukocytes of patients with major depression. Am J Psychiatry 155:666–671
Avissar S, Schreiber G, Nechamkin Y, Neuhaus I, Lam GK, Schwartz P, Turner E, Matthews J, Naim S, Rosenthal NE (1999) The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder. Arch Gen Psychiatry 56:178–183
Axelrod J, Whitby LG, Hertting G (1961) Effect of psychotropic drugs on the uptake of 3H-norepinephrine by tissues. Science 133:383–384
Banerjee SP, Kung LS, Riggi SJ, Chanda SK (1977) Development of β-adrenergic receptor subsensitivity by antidepressants. Nature 268:455–456
Barden N, Reul JMHM, Holsboer F (1995) Do antidepressants stabilize mood through actions on the hypothalamic-pituitary-adrenocortical system? TINS 18:6–11
Benca RM, Obermeyer WH, Thisted RA, Gillin C (1992) Sleep and psychiatric disorders: A meta-analysis. Arch Gen Psychiatry 49:651–668
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
Berger M, Rieman D (1993) REM sleep in depression: An overview. J Sleep Res 2:211–223
Bergstrom DA, Kellar KJ (1979a) Adrenergic serotonergic receptor binding in rat brain after chronic desmethylimipramine treatment. J Pharmacol Exp Ther 209:256–261
Bergstrom DA, Kellar KJ (1979b) Effect of electroconvulsive shock on monoaminergic receptor binding sites in rat brain. Nature 278:464–466
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354
Bernardini R, Chiarenza A, Kamilaris TC, Renaud N, Lempereur L, Demitrack M, Gold PW, Chrousos GP (1994) In vivo and in vitro effects of arginine-vasopressin receptor antagonists on the hypothalamic-pituitary-adrenal axis in the rat. Neuroendocrinology 60:503–508
Birnbaumer L (1990) G protein in signal transduction. Ann Rev Pharmacol Toxicol 30:675–705
Birnbaumer L, Abramowitz J, Brown AM (1990) Receptor-effector coupling by G proteins. Biochim Biophys Acta 1031:163–224
Blackshear MA, Sanders-Bush E (1982) Serotonin receptor sensitivity after acute and chronic treatment with mianserin. J Pharmacol Exp Ther 221:303–308
Blakely RD, Ramamoorthy S, Qian Y, Schroeter SR, Bradley ChC (1997). Regulation of antidepressant-sensitive serotonin transporters. In: Reith MEA (ed) Neurotransmitter transporters: Structure, function and regulation. Humana Press, Totowas, NJ, pp 29–72
Bouvier M, Leeb-Lundberg LMF, Benovic JL, Caron MG, Lefkowitz RJ (1987) Regulation of adrenergic receptor function by phosphorylation. II. Effects of agonist occupancy on phosphorylation of α1-and β2-adrenergic receptors by protein kinase C and the cyclic AMP-dependent protein kinase. J Biol Chem 62:3106–3113
Boyer PA, Skolnick P, Fossom LH (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
Brady LS (1994) Stress, antidepressant drugs, and the locus coeruleus. Brain Res Bull 35:545–556
Brady LS, Whitfield HJ Jr, Fox RJ, Gold PW, Herkenham M (1991) Long-term antidepressant administration alters corticotropin releasing hormone, tyrosine hydroxylase and mineralocorticoid receptor gene expression in rat brain. J Clin Invest 87:831–837
Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield HJ (1992) The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: Therapeutic implications. Brain Res 572:117–125
Briley M, Fillion G (eds) (1988) New concepts in depression. MacMillan Press, London
Briley M, Montgomery ST (eds) (1998) Antidepressant therapy at the dawn of the third millennium. Martin, Dunitz, Ltd., London
Brandoli C, Sanna A, De Bernardi MA, Follesa P, Brooker G, Mocchetti I (1998) Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells. J Neurosci 18:7953–7961
Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, Nemeroff CB, Charney DS (1997) Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154:624–629
Budziszewska B, Siwanowicz J, Przegalinski E (1994) The effect of chronic treatment with antidepressant drugs on the corticosteroid receptor levels in the rat hippocampus. Pol J Pharmacol 46:147–152
Bunney WE, Davis JM (1965) Norepinephrine in depressive reactions. Arch Gen Psychiatry 13:483–494
Burnstein KL, Cidlowsky JA (1989) Regulation of gene expression by glucocorticoids. Ann Rev Physiol 51:683–699
Calogero AE, Galluci WT, Tomai P, Loriaux DL, Chrousos GP, Gold P (1988a) Inhibition of corticotropin releasing hormone secretion by GABAA and GABAB receptor action in vitro: Clinical implications. In: D'Agata R, Chrousos GP (eds) Recent advances in adrenal regulation and function. Raven, New York, pp 279–284
Calogero AE, Galluci WT, Chrousos GP, Golg PW (1988b) Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vitro. J Clin Invest 82:839–846
Carlsson A, Fuxe K, Ungerstedt U (1968) The effect of imipramine on central 5-hydroxytryptamine neurons. J Pharmacy Pharmacol 20:150–151
Cheeta S, Ruigt G, van Proosdij J, Willner P (1997) Changes in sleep architecture following chronic mild stress. Biol Psychiatry 41:419–27
Chen J, Rasenick MM (1995) Chronic antidepressant treatment facilitates G protein activation of adenylyl cyclase without altering G protein content. J Pharmacol Exp Ther 275:509–517
Coleman DE, Sprang SR. How G proteins work: a continuing story. Trends Biochem Sci. 1996;21:41–44
Coppen A (1967) The biochemistry of affective disorders. Br J Psychiatry 113:1237–1264
Costa E, Racagni G (eds) (1982a) Typical and atypical antidepressants: Molecular mechanisms. Adv Biochem Psychopharmacol vol 31
Costa E, Racagni G (eds) (1982b) Typical and atypical antidepressants: Clinical practice. Adv Biochem Psychopharmacol vol 32
Curtis AL, Valentino RJ (1994) Corticotropin-releasing factor neurotransmission in locus coeruleus: A possible site of antidepressant action. Brain Res Bull 35:581–587
Daly JW, Padgett W, Creveling CR, Cantacuzene D, Kirk KL (1980) Fluoroepinephrines: Specific agonists for the activation of alpha and beta adrenergic-sensitive cyclic AMP-generating system in rat slices. J Pharmacol Exp Ther 212:382–389
Deakin JFW (1991) The clinical relevance of animal models of depression. In: Willner P (ed) Behavioural models in psychopharmacology: theoretical, industrial and clinical perspectives. Cambridge University Press, Cambridge, pp 157–174
Decollogne S, Tomas A, Lecerf C, Adamowicz E, Seman M (1997) NMDA receptor complex blockade by oral administration of magnesium: Comparison with MK-801. Pharmacol Biochem Behav 58:261–268
Delbende C, Contesse V, Mocaer E, Kamoun A, Vaudry H (1991) The novel antidepressant, tianeptine, reduces stress-evoked stimulation of the hypothalamo-pituitary-adrenal axis. Eur J Pharmacol 202:391–396
Döbbeling U, Berchtold MW (1996) Down-regulation of the protein kinase A pathway by activators of protein kinase C and intracellular Ca2+ in fibroblast cells. FEBS Letters 391:131–133
Done CJG, Sharp T (1992) Evidence that 5HT2 receptor activation decreases noradrenaline release in rat hippocampus in vivo. Br J Pharmacol 107:240–245
Duman R (2001). Regulation of neural plasticity by stress and antidepressant treatment. In: Briley M, Sulser F (eds) Molecular genetics of mental disorders. Martin Dunitz, London, pp 171–198
Duman RS, Terwilliger RZ, Nestler EJ (1989) Chronic antidepressant regulation of GS ÎĽ and cyclic AMP-dependent protein kinase. Pharmacologist 31:182
Duman RS, Nibuya M, Vaidya VA (1997) A role for CREB in antidepressant action. In: Skolnick P (ed) Antidepressants: New pharmacological strategies. Humana Press, Totowa, NJ, pp 173–194
Dunn AJ, Berridge CW (1990a) Is corticotropin-releasing factor a mediator of stress responses? Ann NY Acad Sci 579:183–191
Dunn AJ, Berridge CW (1990b) Physiological and behavioral responses to corticotropin-releasing factor administration: Is CRF a mediator of anxiety or stress responses? Brain Res Rev 15:71–100
Dwivedi Y, Pandey SC, Pandey GN (1995) Effect of chronic administration of antidepressants on the levels of various subtypes of G-proteins in rat brain. Soc Neurosci 21:731.8 (Abstract)
Dwivedi Y, Roberts R, Conley RC, Tamminga C, Pandey GN (2000) Protein kinase A in the post mortem brain of suicide victims. Biol. Psychiatry 47:75S (Abstract)
Dziedzicka-Wasylewska M, Rogoz R, Klimek V, Maj J (1997) Repeated administration of antidepressant drugs affects the levels of mRNA coding for D1 and D2 dopamine receptors in the rat brain. J Neural Transm 104:515–524
Edwards E, Muneyyrci J, Van Houten P, Michel C, Henn FA (1990) The effect of learned helplessness breeding on opioid mechanisms. Am Coll Neuropsychopharmacol 29:222 (Abstract)
Edwards E, Harkins K, Henn FA (1991a) Learned helplessness modulation of 3H-paroxetine binding in the rat brain. J Neurochem 56:1581–1586
Edwards E, Harkins K, Wright G, Henn FA (1991b) 5HT1b Receptors in an animal model of depression. Neuropharmacology 30:101–105
Eiring A, Sulser F (1997) An increased synaptic availability of norepinephrine is not essential for antidepressant induced increases in hippocampal GR mRNA. J Neural Transm 104:1255–1258
Eiring A, Manier DH, Bieck PR, Howells RD, Sulser F (1992) The’ Serotonin/ Norepinephrine/ Glucocorticoid Link’ beyond the beta adrenoceptors. Molec Brain Res 16:211–214
Emanghoreishi M, Warsh JJ, Sibony D, Li PP (1996) Lack of effect of chronic antidepressant treatment on Gs and Gi α-subunit protein and mRNA levels in the rat cerebral cortex. Neuropsychopharmacol 15:281–287
Ferris RM, Cooper BR (1993) Mechanism of antidepressant activity of bupropion. J Clin Psychiatry 11:1–14
Foulkes NS, Laoide BM, Schlotter F, Sassone-Corsi P (1991) Transcriptional antagonist cAMP-responsive element modulator down-regulates c-fos cAMP-induced expression. Proc Natl Acad Sci USA 88:5448–5452
Frank DA, Greenberg ME (1994) CREB: A mediator of long-term memory from molluscs to mammals. Cell 79:5–8
Frazer A (1997) Pharmacology of antidepressants. J Clin Psychopharmacol 17:2S–18S
Frechilla D, Otano A, Del Rio J (1998) Effect of chronic antidepressant treatment on transcription factor binding activity in rat hippocampus and frontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 22:787–802
Freedman NJ, Liggett SB, Drachman DE, Caron MG, Lefkowitz RJ (1995) Phosphorylation and desensitization of the human b1-adrenergic receptor. J Biol Chem 270:17953–17961
Friedman E, Yocca FD, Cooper TD (1984) Antidepressant drugs with varying pharmacological profiles alter rat pineal beta adrenergic mediated function. J Pharmacol Exp Ther 228:545–550
Gilman AG (1987) G proteins in signal transduction. Ann Rev Biochem 56:615–649
Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59:675–680
Haddjeri N, Blier P, de Montigny C (1996) Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain. J Pharmacol Exp Ther 277:861–871
Hallcher LM, Sherman WR (1980) The effects of lithium ion and other agents on the activity of myoinositol-1-phosphatase from bovine brain. J Biol Chem 255:10896–10901
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 Nat Acad Sci USA 83:9779–9783
Harrelson AL, Rosterre W, McEwen BS (1987) Adrenocortical steroids modify neuro-transmitter stimulated cyclic AMP accumulation in the hippocampus and limbic brain of the rat. J Neurochem 48:1648–1655
Heese K, Otten U, Mathivet P, Raiteri M, Marescaux C, Bernasconi R (2000) GabaB receptor antagonists elevate both mRNA and protein levels of the neurotrophins nerve growth factor (NCG) and brain-derived neurotophic factor (BDNF) but not neurotrophin-3 (NT-3) in brain and spinal cord of rats. Neuropharmacology 39:449–462
Heinrichs SC, Menzaghi FM, Pich EM, Baldwin HA, Rassnick S, Britton KT, Koob GF (1994) Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity. Neuropsychopharmacology 11:179–185
Henn FA (1989) Animal models. In: Mann JJ (ed) Models of depressive disorders. Plenum, New York, pp 93–107
Heydorn WE, Brunswick FT, Frazer A (1982) Effect of treatment of rats with antidepressants on melatonin concentrations in the pineal gland and serum. J Pharmacol Exp Ther 222:534–543
Higuchi H, Yang H-YT, Sobol S (1988) Rat neuropeptide Y precursor gene expression. J Biol Chem 262:6288–6295
Hoeffler JP, Deutsch PJ, Lin J, Habener JF (1989) Distinct adenosine 3’,5’-monophosphate and phorbolester-responsive signal transduction pathways converge at the level of transcriptional activation by the interaction of DNA-binding proteins. Molec Endocrinol 3:868–880
Hokfelt T, Johansson O, Holets V, Meister B, Melander T (1987) Distribution of neuropeptides with special reference to their coexistence with classical transmitters. In: Meltzer HY (ed) Psychopharmacology: The third generation of progress. Raven Press, New York, pp 401–416
Holsboer F, Spengler D, Heuser I (1992) The role of corticotropin-releasing hormone in the pathogenesis of Cushing's disease, anorexia nervosa, alcoholism, affective disorders and dementia. Prog Brain Res 93:385–417
Holzbauer M, Vogt M (1956) Depression by reserpine of the noradrenaline concentration in the hypothalamus of the cat. J Neurochem 1:8–11
Honegger UE, Roscher AA, Wiesmann UN (1983) Evidence for lysosomotropic action of desipramine in cultured human fibroblasts. J Pharmacol Exp Ther 225:436–441
Honkaniemi J, Pelto-Huikko M, Rechardt L, Isola J, Lammi A, Fuxe K, Gustaffson J, Wikstrom AC, Hokfelt T (1992) Colocalization of peptide and glucocorticoid receptor immunoreactivity in rat central amygdaloid nucleus. Neuroendocrinol 55:451–459
Hosoda K, Duman RS (1993) Regulation of b1-adrenergic receptor mRNA and ligand binding by antidepressant treatments and norepinephrine depletion in rat frontal cortex. J Neurochem 69:1335–1343
Huang N-Y, Layer RT, Skolnick P (1997) Is an adaptation of NMDA receptors an obligatory step in antidepressant action? In: Skolnick P (ed) Antidepressants: New pharmacological strategies. Humana Press, Totowa, NJ, pp 125–143
Huff RA, Vaughan RA, Kuhar MJ, Uhl GR (1997) Phorbol esters increase dopamine transporter phosphorylation and decrease transport Vmax. J Neurochem 68:225–232
Hunter T, Karin M (1992)The regulation of transcription by phosphorylation. Cell 70:375–387
Hyman SE, Nestler EJ (1993) The molecular foundations of psychiatry. American Psychiatric Press, Washington DC
Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ (1972) A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2:632–635
Kapur S, Mann JJ (1992) Role of the dopaminergic system in depression. Biol Psychiatry 32:1–17
Kellar KJ, Bergstrom DA (1983) Electroconvulsive shock: Effects on bichemical correlates of neurotransmitter receptors in the brain. Neuropharmacology 22:401–406
Kellar KJ, Stockmeier CA (1986) Effects of electroconvulsive shock and serotonin axon lesions on beta-adrenergic and serotonin-2 receptors in rat brain. Ann NY Acad Sci 462:76–90
Kellar KJ, Cascio CS, Bergstrom DA, Butler JA, Iaradola P (1981a) Electroconvulsive shock and reserpine: Effects on b-adrenergic receptors in rat brain. J Neurochem 37:830–836
Kellar KJ, Cascio CS, Butler JA, Kurtzke RN (1981b) Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain. Eur J Pharmacol 69:515–518
Kendall DA, Nahorski SR (1985) 5-hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortical slices: Pharmacological characterization and effects of antidepressants. J Pharmacol Exp Ther 233:473–479
Kitayama I, Janson AM, Cintra A, Fuxe K, Agnati LF, Ogren SO, Harfstrand A, Eneroth P, Gustafsson JA (1988) Effects of chronic imipramine treatment on glucocorticoid receptor immunoreactivity in various regions of the rat brain. J Neural Transm 73:191–203
Kitayama I, Nakamura S, Yaga T, Murase S, Nomura J, Kayahara T, Nakano K (1994) Degeneration of locus coeruleus axons in stress-induced depression model. Brain Res Bull 35:573–580
Klimek V, Papp M (1994) The effects of MK-801 and imipramine on beta adrenergic and 5HT2 receptors in the chronic mild stress model of depression in rats. Pol J Pharmacol Pharm 46:67–69
Klimek V, Nielsen M, Maj J (1985) Repeated treatment with imipramine decreased the number of [3H]piflutixol binding sites in the rat striatum. Eur J Pharmacol 109:131–132
Kramer MS, Cutler N, Feighner J, Shrivastava R (1998). Distinct mechanisms for antidepressant activity by blockade of central substance P receptors. Science 281:1640–1645
Kuhn R (1958) The treatment of depressive states with G22355 (imipramine hydrochloride). Am J Psychiatry 115:459–464
Lachman HM, Papolos DF, Weiner ED, Ramazankhana R, Hartnick C, Edwards E, Henn FA (1992) Hippocampal neuropeptide Y mRNA is reduced in a strain of learned helpless resistant rats. Mol Brain Res 14:94–100
Lachman HM, Papolos DF, Boyle A, Sheftel G, Juthani M, Edwards E, Henn FA (1993) Alterations in glucocorticoid inducible RNAs in the limbic system of learned helpless rats. Brain Res 609:110–116
Layer RT, Popik P, Olds T, Skolnick P (1995) Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715). Pharmcol Biochem Behav 52:621–627
Lee KAW, Masson N (1993) Transcriptional regulation by CREB and its relatives. Biochem Biophys Acta 1174:221–233
Leeb-Lundberg LMF, Cotecchia S, Lomasney JW, DeBernardis JF, Lefkowitz RJ, Caron MG (1985) Phorbol esters promote α1-adrenergic receptor phosphorylation and receptor uncoupling from inositol phospholipid metabolism. Proc Natl Acad Sci USA 82:5651–5655
Leeb-Lundberg LMF, Cotecchia S, DeBlasi A, Caron MG, Lefkowitz RJ (1987) Regulation of adrenergic receptor function by phosphorylation. I. Agonist-promoted desensitization and phosphorylation of α-adrenergic receptors coupled to inositol phospholipid metabolism in DDT1 MF-2 smooth muscle cells. J Biol Chem 262:3098–3105
Lehmann HE, Kline NS (1983) Clinical discoveries with antidepressant drugs. In: Parnham MJ, Bruinvels J (eds) Discoveries in pharmacology, vol 1. Elsevier, Amersterdam, pp 209–221
Lejeune F, Audinot V, Gobert A, River JM, Spedding M, Millan MJ (1994) Clozapine inhibits serotoninergic transmission by an action at a1-adrenoceptors not at 5HT1A receptors. Eur J Pharmacol 260:79–83
Leonard BE (1997) Noradrenaline in basic models of depression. Eur Neuropsychopharmacol 7(Suppl 1):S11–S16
Leonard BE, Spencer P (eds) (1990) Antidepressants: Thirty years on. CNS Publishers, London
Lesch KP, Manji HK (1992) Signal-transducing G proteins and antidepressant drugs: evidence of modulation of μ subunit gene expression in rat brain. Biol Psychiatry 32:549–579
Lesch KP, Anlakh CS, Tollives TG, Hill JL, Murphy DL (1991) Regulation of G proteins by chronic antidepessant drugs in rat brain: tricyclics but not clorgyline increase Go μ subunits. Eur J Pharmacol 207:361–364
Li PP, Warsh JJ, Sibony D, Chiu A (1985) Assessment of rat brain alpha 1-adrenoceptor binding and activation of inositol phospholipid turnover following chronic imipramine treatment. Neurochem Res 13:1111–1118
Li PP, Young LT, Warsh JJ (1994) Effects of antibipolar and antidepressant drugs on the levels of signal transducing G proteins and their messenger ribonucleic acid transcripts. Neuropsychopharmacology 10:380S
Li Q, Hrdina PD (1997) GAP-43 phosphorylation by PKC in rat cerebrocortical synaptosomes: effect of antidepressants. Res Commun Mol Pathol Pharmacol 96:3–13
Maj J (1984) Central effects following repeated treatment with antidepressant drugs. Pol J Pharmacol Pharm 36:87–99
Maj J, Rogoz Z, Skuza G, Sowinska H (1984) Repeated treatment with antidepressant drugs potentiates the locomotor response to (+)-amphetamine. J Pharm Pharmacol 36:127–130
Maj J, Wedzony K, Klimek V (1987) Desipramine given repeatedly enhances behavioural effects of dopamine and d-amphetamine injected into the nucleus accumbens. Eur J Pharmacol 140:179–185
Maj J, Papp M, Skuza G, Bigajska K, Zazula M (1989a) The influence of repeated treatment with imipramine, (+)-and (-)-oxaprotiline on behavioural effects of dopamine D-1 and D-2 agonists. J Neural Transm 76:29–38
Maj J, Rogoz Z, Skuza G, Sowinska H (1989b) Antidepressants given repeatedly increase the behavioural effect of dopamine D-2 agonist. J Neural Transm Gen Sect 78:1–8
Maj J, Rogoz Z, Skuza G, Sowinska H (1992a) The effect of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test. Pol J Pharm 44:337–346
Maj J, Rogóz Z, Skuza G. Sowiñska H (1992b) Effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur Neuropsychopharmacology 2:37–41
Maj J, Dziedzicka-Wasylewska M, Rogoz R, Rogoz Z, Skuza G (1996) Antidepressant drugs given repeatedly change the binding of the dopamine D2 receptor agonist [3H]N-0437 to dopamine D2 receptors in the rat brain. Eur J Pharmacol 304:49–54
Maj J, Dziedzicka-Wasylewska M, Rogoz R, Rogoz Z (1998) Effect of antidepressant drugs administered repeatedly on the dopamine D3 receptors in the rat brain. Eur J Pharmacol 351:31–37
Manier DH, Eiring A, Shelton RC, Sulser F (1996) Beta adrenoceptor-linked protein kinase A (PKA) activity in human fibroblasts from normal subjects and patients with major depression. Neuropsychopharmacology 15:555–561
Manier DH, Shelton RC, Ellis T, Peterson CS, Eiring A, Sulser F (2000) Human fibroblasts as a relevant model to study signal transduction in affective disorders. J Affect Disord 2000:61:51–58
Manier DH, Shelton RC, Sulser F (2001) Cross-talk between PKA and PKC in human fibroblasts: What are the pharmacotherapeutic implications? J Affect Disord 65:275–279
Manier DH, Shelton RC, Sulser F (2002) Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P? J Neural Transm 109:91–99
Manji HK, Lenox RH (1994) Long-term action of lithium: A role for transcriptional and postranscriptional factors regulated by protein kinase C. Synapse 16:11–28
Manji HK, Lenox RH (1999) Protein kinase C signaling in the brain: Molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry 46:1328–1351
Mann CD, Vu TB, Hrdina PD (1995) Protein kinase C in rat brain cortex and hippocampus: Effect of repeated administration of fluoxetine and desipramine. Br J Pharmacol 115:595–600
Mansbach RS, Brooks EN, Chen YL (1997) Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist. Eur J Pharmacol 323:21–26
Martin JV, Edwards E, Johnson JO, Henn FA (1990) Monoamine receptors in an animal model of affective disorders. J Neurochem 55:1142–1148
Menkes DB, Rasenick MM, Wheeler MA, Bitensky MW (1983) Guanosine triphosphate activation of brain adenylate cyclase: Enhancement by long-term antidepressant treatment. Science 219:65–67
Meyer TE, Habener JF (1993) Cyclic adenosine 3’,5’-monophosphate response element binding protein (CREB) and related transcriptional-activating deoxyribonucleic acid-binding proteins. Endocrine Reviews 14:269–290
Mobley PL, Manier DH, Sulser F (1983) Adrenal corticoids regulate the norepinephrine sensitive adenylate cyclase system in brain. J Pharmacol Exp Ther 226:71–77
Montgomery SA (1997) Is there a role for a pure noradrenergic drug in the treatment of depression? Eur Neuropsychopharmacol 7(Suppl 1):S3–S9
Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burcracher N, Sakmann B, Seeberg PH (1992) Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science 256:1217–1221
Moreau JL (1997) Validation of an animal model of anhedonia, a major symptom of depression. Encephale 23:280–289
Moreau JL, Jenck F, Martin JR, Mortas P, Haefely W (1993) Effects of moclobemide, a new generation reversible MAO-A inhibitor, in a novel animal model of depression. Pharmacopsychiatry 26:30–33
Moreau JL, Bos M, Jenck F, Martin JR, Mortes P, Wichmann J (1996). 5HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression in rats. Eur Neuropsychopharmacol 6:169–175
Morinobu S, Nibuya M, Duman RS (1995) Chronic antidepressant treatment down-regulates the induction of c-fos mRNA in response to acute stress to rat frontal cortex. Neuropsychopharmacology 12:221–228
Muscat R, Papp M, Willner P (1992) Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Psychopharmacology (Berl) 109:433–438
Nalepa I (1994) The effect of psychotropic drugs on the interaction of protein kinase C with second messenger systems in the rat cerebral cortex. Pol J Pharmacol Pharm 46:1–14
Nalepa I, Vetulani J (1991a) Different mechanisms of b-adrenoceptor downregulation by chronic imipramine and electroconvulsive treatment: possible role for protein kinase C. J Neurochem 57:904–910
Nalepa I, Vetulani J (1991b) Involvement of protein kinase C in the mechanisms of in vitro effects of imipramine on generation of second messengers by noradrenaline in the cerebral cortical slices of the rat. Neuroscience 44:585–590
Nalepa I, Vetulani J (1993a) The effect of calcium channel blockade on the action of chronic ECT and imipramine on responses of α1 and β-adrenoceptors in the rat cerebral cortex. Pol J Pharmacol Pharm 45:201–205
Nalepa I, Vetulani J (1993b) Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram. J Neurochem 60:2029–2035
Nalepa I, Vetulani J (1994) The responsiveness of cerebral cortical adrenergic receptors after chronic administration of atypical antidepressant mianserin. J Psychiatry Neurosci 19:120–128
Nalepa I, Chalecka-Franaszek E, Vetulani J (1993) The antagonistic effect of separate and consecutive chronic treatment with imipramine and ECT on the regulation of α1-adrenoceptor activity by protein kinase C. Pol J Pharmacol Pharm 45:521–532
Nalepa I, Chalecka-Franaszek E, Vetulani J (1996) Modulation by mianserin pretreatment of the chronic electroconvulsive shock effects on the adrenergic system in the cerebral cortex of the rat. Human Psychopharmacology 11:273–282
Nalepa I, Manier DH, Gillespie DG, Rossby SP, Schmidt DE, Sulser F (1998) Lack of beta adrenoceptor desensitization in brain following the dual noradrenaline and serotonin reuptake inhibitor venlafaxine. Eur Neuropsychopharmacol 8:227–232
Neliat G, Bodinier MC, Panconi E, Briley M (1996) Lack of effect of milnacipran, a double noradrenaline and serotonin reuptake inhibitor, on the b-adrenoceptor-linked adenylate cyclase system in the rat cerebral cortex. Neuropharmacology 35:589–593
Nemeroff CB, Widerlov E, Bissette G, Karlsson I, Eklund K, Kilts CD, Loosen P, Vale W (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226:1342–1344
Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M(1988) Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 45:577–579
Nestler EJ, Greengard P (1984) Protein phosphorylation in the nervous system. Wiley, New York
Nestler EJ, Terwilliger RZ, Duman RS (1989) Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 53:1644–1647
Nestler EJ, McMahon A, Sabban EL, Tallman JT, Duman RS (1990) Chronic antidepressant administration decreases the expression of tyrosine hydroxylase in the rat locus coeruleus. Proc Natl Acad Sci USA 87:7522–7526
Newman ME, Lerer B (1989) Modulation of second messenger function in rat brain by in vivo alteration of receptor sensitivity: relevance to the mechanism of action of electroconvulsive therapy and antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 13:1–30
Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvlusive seizure and antidepressant drug treatment. J Neurosci 15:7539–7547
Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of CREB in rat hippocampus. J Neurosci 16:2365–2372
Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614
Nowak G, Trullas R, Layer RT, Skolnick P, Paul IA (1993) Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropane-carboxylic acid. J Pharmacol Exp Ther 265:1380–1386
Nowak G, Ordway GA, Paul IA (1995) Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res 675:157–164
Okuyama S, Chaki S, Kawashima N, Suzuki Y, Ogawa S, Nakazato A, Kumagai T, Okubo T, Tomisawa K (1999) Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001. J Pharmacol Exp Ther 289:926–935
Oswald I, Brezinova V, Dunleavy DLF (1973) On the slowness of action of tricyclic antidepressant drugs. Br J Psychiatry 120:673–677
Owens MJ, Morgan WN, Plott SE, Jeni J, Nemeroff CB (1995) In vitro inhibition of the rat and human serotonin and norepinephrine transporters by the antidepressant nefazodone and its metabolites. Soc Neurosci 21:309.1 (abstract)
Panconi E, Roux J, Altenbaumer M, Hampe S, Porsolt RD (1993) MK-801 and enantiomers: Potential antidepressants or false positives in classical screening models? Pharmacol Biochem Behav 46:15–20
Pandey GN, Heinze WJ, Brown BD, Davis JM (1979) Electroconvulsive shock treatment decreases β-adrenergic receptor sensitivity in rat brain. Nature 280:234–235
Pandey GN, Pandey SC, Isaac L, Davis M (1992) Effect of electroconvulsive shock on 5HT2 and α1-adrenoceptors and phosphoinositide signaling system in rat brain. Eur J Pharmacol 226:303–310
Papp M (1996) Comparison of antidepressant and psychomimetic effects of agents acting at various sites of the NMDA receptor complex. Behav Pharmacol 7(suppl 1):82–83
Papp M, Moryl E (1994) Antidepressant activity of noncompetitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur J Pharmacol 263:1–7
Papp M, Moryl E (1996) Antidepressant-like effects of 1-aminocyclopropanecarboxylic acid and D-cycloserine in an animal model of depression. Eur J Pharmacol 316:145–151
Papp M, Klimek V, Willner P (1994a) Effects of imipramine on serotonergic and beta-adrenergic receptor binding in a realistic animal model of depression. Psychopharmacology (Berlin) 114:309–14
Papp M, Klimek V, Willner P (1994b) Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine. Psychopharmacology-Berl 115:441–446
Papp M, Nalepa I, Vetulani J (1994c) Reversal by imipramine of beta adrenoceptor upregulation induced in a chronic mild stress model of depression. Eur J Pharm 261:141–147
Papp M, Moryl E, Willner P (1996) Pharmacological validation of the chronic mild stress model of depression. Eur J Pharmacol 296:129–136
Pariante CM, Pearce BD, Pisell TL, Owens MJ, Miller AH (1997) Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine. Mol Pharmacol 52:571–581
Paul IA, Trullas R, Skolnick P, Nowak G (1992) Down-regulation of cortical β-adrenoceptors by chronic treatment with functional NMDA antagonists. Psychopharmacology 106:285–287
Paul IA, Layer RT, Skolnick P, Nowak G (1993) Adaptation of the NMDA receptor in rat cortex following chronic electroconvulsive shock or imipramine. Eur J Pharmacol 247:305–312
Paul IA, Nowak G, Layer RT, Popik P, Skolnick P (1994) Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther 269:95–102
Peiffer A, Veilleaux S, Barden N (1991) Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain. Psychoneuroendocrinology 16:505–515
Pepin MC, Beaulieu S, Barden N (1989) Antidepressants regulate glucocorticoid receptor messenger RNA concentrations in primary neuronal cultures. Mol Brain Res 6:77–83
Pepin MC, Pothier F, Barden N (1992) Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Mol Pharmacol 42:991–995
Perez J, Tinelli D, Brunello N, Racagni G (1989) CAMP-dependent phosphorylation of soluble and crude microtubule fractions of rat cerebral cortex after prolonged desmethylimipramine treatment. Europ J Pharmacol 172:305–316
Perez J, Moris, Caivano M, Fumagalli I, Pezzetta B, Tascedda F, Brunello N, Racagni G (1994) cAMP protein kinase as a intracellular target for the action of antidepressant drugs. Neuropyschopharmacology 10:171S (Abstract)
Peterson MG, Tupy JL (1994) Transcriptional factors: A new frontier in pharmaceutical development. Biochem Pharmacol 47:127–128
Pietu G, Decraene C, Fayerin N, Manage-Samson R, Eveno E, Matingan C, Devigues M, Auffray C (2001) Characterization of expression profiles of genes involved in brain functions by quantitative hybridization of high-density cDNA arrays. In: Briley M, Sulser F (eds) Molecular genetics of mental disorders. Martin Dunitz Ltd, London pp 1–19
Pilc A, Branski P, Palucha A, Aronowski J (1999) The effect of prolonged imipramine and electroconvulsive shock treatment on calcium/calmodulin-dependent protein kinase II in the hippocampus of rat brain. Neuropharmacology 38:597–603
Plaznik A, Kostowski W, Archer T (1989) Serotonin and depression: Old problems and new data. Prog Neuropsychopcharmacol Biol Psychiatry 13:623–633
Pletscher A, Shore PA, Brodie BB (1955) Serotonin release as a possible mechanism of reserpine action. Science 122:374–375
Plotsky PM (1987) Facilitation of immunoreactive corticotropin-releasing factor secretion into the hypophyseal-portal circulation after activation of catecholaminergic pathways of central norepinephrine injection. Endocrinology 121:924–930
Popoli M, Vocaturo C, Perez J, Smeraldi E, Racagni G (1995) Presynaptic Ca2+/calmodulin-dependent protein kinase II: Autophosphorylation and activity increase in the hippocampus after long-term blockade of serotonin reuptake. Mol Pharmacol 48:623–629
Porsolt RD, Lanegre A (1992) Behavioral models of depression. In: Elliot JM, Heal DJ, Marsden CA (eds) Experimantal approaches to anxiety and depression. John Wiley: Chichester, pp 73–86
Porsolt RD, Lenegre A, McArthur RA (1991) Pharmacological models of depression. In: Oliver B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhauser, Basel, pp 137–159
Porter R, Bock G, Clark S (eds) (1986) Antidepressants and receptor function. Ciba Foundation Symposium 123, Wiley, Chichester, UK
Premont RT, Inglese J, Lefkowitz RJ (1995) Protein kinases that phosphorylate activated G protein-coupled receptors. FASEB J 9:175–182
Pryor JC, Sulser F (1991) Evolution of monoamine hypotheses of depression. In: Horton RW, Katona C (eds) Biological aspects of affective disorders. Academic Press, London, pp 77–94
Przegalinski E, Budziszewska B (1993) The effect of long-term treatment with antidepressant drugs on the hippocampal mineralocorticoid and glucocorticoid receptors in rats. Neurosci Lett 161:215–218
Przegalinski E, Moryl E, Papp M (1995) The effect of 5-HT1A receptor ligands in a chronic mild stress model of depression. Neuropharmacology 34:1305–1310
Quetsch RM, Achor RWP, Litin EM, Faucett RL (1959) Depressive reactions in hypertensive patients. A comparison of those treated with rauwolfia and those receiving no specific antihypertensive treatment. Circulation 19:366–375
Qian Y, Galli A, Ramamoorthy S, Risso S, DeFelice LJ, Blakely RD (1997) Protein kinase C activation regulates human serotonin transporters in HEK-293 cells via altered cell surface expression. J Neurosci 17:45–57
Rahman S, Li PP, Young LT, Kofman O, Kish SJ, Warsh JJ (1997) Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder. J Neurochem 68:297–304
Randrup A, Munkvad I, Fog R, Gerlach J, Molander R, Kjellenberg B, Scheel-Krueger J (1975) Mania, depression and brain dopamine. Curr Develop Psychopharmacol 2:207–229
Rasenick MM (1994) G proteins as the molecular target of antidepressant action: Chronic treatment increases coupling between Gs and adenylate cyclase. Neuropsychopharmacology 10:580S (Abstract)
Riva M, Brunello N, Rovescalli AC, Galimberti R, Carfagna N, Carminati P, Pozzi O, Ricciardi S, Roncucci R, Rossi A, Racagni G (1989) Effect of reboxetine, a new antidepressant drug, on the central noradrenergic system: behavioural and biochemical studies. J Drug Development 1:243–253
Rivier CL, Plotsky PM (1986) Mediation by corticotropin-releasing factor (CRF) of adenohypophyseal hormone secretion. Ann Rev Physiol 48:475–494
Rivier J, Rivier C, Vale W (1984) Synthetic competitive antagonists of corticotropin-releasing factor: Effect on ACTH secretion in the rat. Science 224:889–891
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
Rossby SP, Sulser F (1993) Die Wirkmechanismen von Antidepressiva: Ein historischer Rückblick und neue neurobiologische Aspekte. ZNS Journal, Forum fur Psychiatrie und Neurologie 1:10–19
Rossby SP, Sulser F (1997) Antidepressants: Events beyond the synapse. In: Skolnick P (ed) Antidepressants: New pharmacological strategies. Humana Press, Totowa, NJ, pp 195–212
Rossby SP, Nalepa I, Huang M, Burt A, Perrin C, Schmidt DE, Sulser F (1995) Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant. Brain Res 687:79–82
Rossby SP, Perrin C, Burt A, Nalepa I, Schmidt DE, Sulser F (1996) Fluoxetine increases steady-state levels of preproenkephalin mRNA in rat amygdala by a serotonin dependent mechanism. J Serotonin Res 3:69–74
Rossby SP, Manier DH, Liang S, Nalepa I, Sulser F (1999) Venlafaxine: Pharmacological actions beyond aminergic receptors. Int J Neuropsychopharmacol 2:1–8
Rossby SP, Liang S, Manier DH, Chakrabarti A, Shelton RC, Sulser F (2001) Molecular psychopharmacology as a prelude to a molecular psychopathology of affective disorders: The significance of differential display methodology to study programs of gene expression. In: Briley M, Sulser F (eds) Molecular genetics of mental disorders. Martin Dunitz, Ltd., London, pp 31–46
Rouquier L, Claustre Y, Benavides J (1994) α1-Adrenoceptor antagonists differentially control serotonin release in the rat hippocampus and striatum: A microdialysis study. Eur J Pharm 261:59–64
Russo-Neustadt A, Beard RC, Cotman CW (1999) Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology 21:679–682
Salin P, Kerkerian L, Nieoullon A (1990) Expression of neuropeptide Y immunoreactivity in the rat nucleus accumbens is under the influence of the of the dopaminergic mesencephalic pathway. Exp Brain Res 81:363–371
Sampson D, Muscat R, Willner P (1991) Reversal of antidepressant action by dopamine antagonists in an animal model of depression. Psychopharmacology 104:491–495
Sato K, Adams R, Betz H, Schloss P (1995a) Modulation of a recombinant glycine transporter (GLYT1b) by activation of protein kinase C. J Neurochem 65:1967–1973
Sato K, Betz H, Schloss P (1995b) The recombinant GABA transporter GAT1 is downregulated upon activation of protein kinase C. FEBS Lett 375:99–102
Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122:509–522
Schildkraut JJ, Kety SS (1967) Biogenic amines and emotion. Science 156:21–30
Schultz J (1976) Psychoactive drug effects on a system which generates cyclic AMP in brain. Nature 261:417–418
Schwaninger M, Schofl C, Blume R, Rossig L, Knepel W (1995) Inhibition by antidepressant drugs of cyclic AMP response element-binding protein/cyclic AMP response element-directed gene transcription. Mol Pharmacol 47:1112–1118
Seasholtz AF, Gamm DM, Ballestero RP, Scarpetta MA, Uhler MD (1995) Differential expression of mRNAs for protein kinase inhibitor isoforms in mouse brain. Proc Natl Acad Sci USA 92:1734–1738
Seckl JR, Fink G (1992) Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA expression in rat hippocampus in vivo. Neuroendocrinology 55:621–626
Shelton R, Manier DH, Sulser F (1996) Cyclic cAMP-dependent protein kinase activity in major depression. Am J Psychiatry 153:1037–1042
Shelton RC, Manier DH, Ellis T, Peterson CS, Sulser F (1999) Cyclic AMP dependent protein kinase in subtypes of major depression and normal volunteers. Int J Neuropsy-chopharmacol 3:187–192
Sheng M, Thompson MA, Greenberg ME (1991). CREB: A Ca++ regulated transcriptional factor phosphorylated by calmodulin-dependent kinases. Science 252:1427–1430
Shih M, Malbon CC (1994) Oligodeoxygnucleotides antisense to mRNA encoding protein kinase A, protein kinase C and b-adrenergic receptor kinase reveal distinctive celltype specific roles in agonist-induced desensitization. Proc Natl Acad Sci USA 91:12193–12197
Shirayama Y, Mitsushio H, Takashima M, Ichikawa H (1996) Reduction of substance P after chronic antidepressants treatment in the striatum, substantia nigra and amygdala of the rat. Brain Res 739:70–78
Sibley DR, Strasser RH, Benovic JL, Daniel K, Lefkowitz RJ (1986) Phosphorylation/dephosphorylation of the b-adrenergic receptor regulates its functional coupling to adenylate cyclase and subcellular distribution. Proc Natl Acad Sci USA 83:9408–9412
Skolnick P (1999) Antidepressants for the new millennium. Eur J Pharmacol 375:31–40
Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R (1996) Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29:23–26
Skutella T, Montkowski A, Stoehr T, Probst JC, Landgraf R, Holsboer F, Jirikowski GF (1994) Corticotropin-releasing hormone (CRF) antisense oligodeoxynucleotide treatment attenuates social defeat-induced anxiety in rats. Cell Mol Neurobiol 14:579–588
Sluzewska A, Nowakowska E (1994) The effects of carbamazepine, lithium and ketoconazole in chronic mild stress model of depression in rats. Behav Pharmacol 5(Suppl 1):86 (Abstract)
Spyraki C, Fibiger HC (1981) Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine. Eur J Pharmacol 74:195–206
Stamford JA, Muscat R, O'Connor JJ, Patel JJ, Wieczorek WJ, Kruk ZL, Willner P (1991) Voltammetric evidence that subsensivity to reward following chronic mild stress is associated with increased release of mesolimbic dopamine. Psychopharmacology 105:275–282
Stogner KA, Holmes PV (2000) Neuropeptide-Y exerts antidepressant-like effects in the forced swim test in rats. Eur J Pharmacol 387:R9–R10
Stone EA (1979a) Reduction by stress of norepinephrine-stimulated accumulation of cyclic AMP in rat cerebral cortex. J Neurochem 32:1335–1337
Stone EA (1979b) Subsensitivity to norepinephrine as a link between adaptation to stress and antidepressant therapy: A hypothesis. Res Commun Psychol Psychiat Behav 4:241–255
Stone EA, Platt JE, Herrera AS, Kirk KL (1986) Effect of repeated restraint stress, desmethylimipramine or adrenocorticotropin on the alpha and beta adrenergic components of the cyclic AMP response to norepinephrine in rat brain slices. J Pharm Exp Ther 237:702–707
Sulser F (1978) Functional aspects of the norepinephrine receptor coupled adenylate cyclase system in the limbic forebrain and its modification by drugs which precipitate or alleviate depression: Molecular approaches to an understanding of affective disorders. Pharmakopsychiatry 11:43–52
Sulser F, Mishra R (1983) The discovery of tricyclic antidepressants and their mode of action. In: Parnham MJ, Bruinvels J, (eds) Discoveries in pharmacology, vol 1. Elsevier, Amersterdam, pp 233–247
Szabadi E, Bradshaw CM, Boston PF, Langley RW (1998). The human pharmacology of reboxetine. Human Psychopharmacology 13;S3–S12
Szmigielski A, Gorska D (1997) The effect of prolonged imipramine treatment on the alpha 1-adrenoceptor-induced translocation of protein kinase C in the central nervous system in rats. Pharmacol Res 35:569–576
Tassin JP, Studler JM, Herve D, Blanc G, Glowinski J (1986) Contribution of noradrenergic neurons to the regulation of dopaminergic (D1) receptor denervation supersensitivity in rat prefrontal cortex. J Neurochem 46:243–248
Taylor SS (1989) cAMP-dependent protein kinase. J Biol Chem 264:8443–8446
Toth M, Shenk T (1994) Antagonist-mediated down-regulation of 5-hydroxytryptamine type 2 receptor gene expression: Modulation of transcription. Mol Pharmacol 45:1095–1100
Trovero F, Herve D, Blanc G, Glowinski J, Tassin JP (1992) In vivo partial inactivation of dopamine D1 receptors induces hypersensitivity of cortical dopamine-sensitive adenylate cyclase: permissive role of alpha 1-adrenergic receptors. J Neurochem 59:331–337
Vetulani J, Sulser F (1975) Action of various antidepressant treatment reduces reactivity of noradrenergic cyclic AMP generating system in limbic forebrain. Nature 257:495–496
Vetulani J, Stawarz RJ, Sulser F (1976a) Adaptive mechanisms of the noradrenergic cyclic AMP generating system in the limbic forebrain of the rat: Adaptation to persistent changes in the availability of norepinephrine (NE). J Neurochem 27:661–666
Vetulani J, Stawarz RJ, Dingell JV, Sulser F (1976b) A possible common mechanism of action of antidepressant treatments. Reduction in the sensitivity of the noradrenergic cyclic AMP generating system in the rat limbic forebrain. Naunyn-Schmiedeberg's Arch Pharmacol 293:109–114
Vetulani J, Lebrecht U, Pilc A (1981) Enhancement of responsiveness of the central serotonergic system and serotonin-2 receptor density in the rat frontal cortex by electroconvulsive treatment. Eur J Pharmacol 76:81–85
Vetulani J, Antkiewicz-Michaluk L, Rokosz-Pelc A, Pilc A (1983) Chronic electroconvulsive treatment enhances the density of [3H]prazosin binding sites in the central nervous system of the rat. Brain Res 275:392–395
Vetulani J, Antkiewicz-Michaluk L, Rokosz-Pelc A, Pilc A (1984a) Alpha up-beta down adrenergic regulation: A possible mechanism of action of antidepressant treatments. Pol J Pharmacol Pharm 36:231–248
Vetulani J, Antkiewicz-Michaluk L, Rokosz-Pelc A (1984b) Chronic administration of antidepressant drugs increases the density of cortical 3H-prazosin binding sites in the rat. Brain Res 310:360–362
Wachtel H (1989) Dysbalance of neuronal second messenger function in the aetiolgy of affective disorders: A pathophysiological concept hypothesising defects beyond first messenger receptors. J Neural Transm 75:21–29
Wahlestedt C, Ekman R, Widerlov E (1989) Neuropeptide Y and the central nervous system: Distribution and possible relationship to neurological and psychiatric disorders. Prog Neuropsychopharmacol Biol Psychol 13:31–54
Wedzony K, Klimek V, Nowak G (1995) Rapid down-regulation of beta-adrenergic receptors evoked by combined forced swimming test and CGP 37849—a competitive antagonist of NMDA receptors. Pol J Pharmacol Pharm 47:537–540
White BD, Dean R, Martin RJ (1990) Adrenalectomy decreases neuropeptide Y mRNA levels in the arcuate nucleus. Brain Res Bull 25:711–715
Widerlov E, Lindstom LM, Wahlestedt C, Ekman R (1988) Neuropeptide Y and peptide YY as possible cerebrospinal markers for major depression and schizophrenia, respectively. J Psychiatric Res 22:69–79
Wielosz M (1981) Increased sensitivity to dopaminergic agonists after repeated electroconvulsive shock (ECT) in rats. Neuropharmacology 10:941–945
Willner P (1983) Dopamine and depression: A review of recent evidence. III. The effects of antidepressant treatments. Brain Res 287:237–246
Willner P (1991) Animals models as simulation of depression. Trends Pharmacol Sci 12:131–136
Willner P (1997a) The mesolimbic dopamine system as a target for rapid antidepressant action. Int Clin Psychopharmacol 12(Suppl 3):S7–S14
Willner P (1997b) Validity, reliability and utility of the chronic mild stress model of depression: A 10 year review and evaluation. Psychopharmacology 134:319–329
Willner P, Papp M (1997) Animal models to detect antidepressants: Are new strategies necessary to detect new agents? In: Skolnick P (ed) Antidepressants: New pharmacological strategies. Humana Press, Totowa, NJ, pp 213–234
Willner P, Towell A, Sampson D, Sophokleus S, Muscat R (1987) Reduction of sucrose preference by chronic mild stress and its restoration by a tricyclic antidepressant. Psychopharmacology 93:358–364
Willner P, Klimek V, Golembiowska K, Muscat R (1991) Changes in mesolimbic dopamine may explain stress-induced anhedonia. Psychobiology 19:79–84
Willner P, Muscat R, Papp M (1992) Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 16:525–534
Wolfe BB, Harden TK, Sporn JR, Molinoff PB (1978) Presynaptic modulation of beta-adrenergic receptors in rat cerebral cortex after treatment with antidepressants. J Pharmacol Exp Ther 207:446–457
Wong DT, Bymaster FP, Engleman EA (1995) Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication. Life Sci 57:411–441
Wong EHF, Sonders MS, Amara SG, Tinholt PM, Piercey MF, Hoffmann WP, Hyslop DK, Franklin S, Porsolt RD, Bonsignori A, Carfagna N, McArthur RA (2000) Reboxetine: A pharmacologically potent, selective and specific norepinephrine reuptake inhibitor (NRI). Biol Psychiatry 47:818–829.
Yoshikawa K, Sabol SL (1986) Expression of the enkephalin precursor gene in C6 glioma cells: Regulation by b-adrenergic agonists and glucocorticoids. Molec Brain Res 1:75–83
Yuan PX, Chen G, Huang LD, Manji HK (1998) Lithium stimulates gene expression through the AP-1 transcription factor pathway. Mol Brain Res 58:225–230
Yuan P, Chen G, Manji HK (1999) Lithium activates the c-Jun NH2-terminal kinases in vitro and in the CNS in vivo. J Neurochem 73:2299–2309
Zeller EA (1983) Monoamine oxidase and its inhibitors in relation to antidepressive activity. In: Parnham MJ, Bruinvels J (eds) Discoveries in pharmacology, vol 1. Elsevier, Amersterdam, pp 223–232
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Nalepa, I., Sulser, F. (2004). New Hypotheses to Guide Future Antidepressant Drug Development. In: Preskorn, S.H., Feighner, J.P., Stanga, C.Y., Ross, R. (eds) Antidepressants: Past, Present and Future. Handbook of Experimental Pharmacology, vol 157. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18500-7_18
Download citation
DOI: https://doi.org/10.1007/978-3-642-18500-7_18
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-62135-2
Online ISBN: 978-3-642-18500-7
eBook Packages: Springer Book Archive