Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents
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Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs.
The present studies were conducted to evaluate the effects of the novel 5-HT2C receptor agonist WAY-163909 in animal models of antidepressant activity (forced swim test (FST), resident–intruder, olfactory bulbectomy (BULB)), in a schedule-induced polydipsia (SIP) model of obsessive–compulsive disorder and in a model for evaluating sexual dysfunction.
WAY-163909 (10 mg/kg, i.p. or s.c.) decreased immobility time in Wistar–Kyoto rats in the FST, effects that were reversed by the 5-HT2C/2B receptor antagonist SB 206553. Moreover, in Sprague-Dawley rats, the profile of WAY-163909 (decreased immobility, increased swimming) in the FST was comparable to the effects of SSRIs. Acute treatment with WAY-163909 (0.33 mg/kg, s.c.) decreased rodent aggression at doses lower than those required for decreasing total behavior. Administration of WAY-163909 (3 mg/kg, i.p.) for 5 or 21 days decreased the BULB-induced hyperactivity in rats. Additionally, acute administration of WAY-163909 (3 mg/kg, i.p.) decreased adjunctive drinking in a SIP model. The effects of WAY-163909 were reversed by the 5-HT2C/2B receptor antagonist SB 206553 and the selective 5-HT2C receptor antagonist SB 242084. Chronic administration of WAY-163909 produced deficits in sexual function at doses higher (10 mg/kg, i.p.) than those required for antidepressant-like effects in the BULB model.
Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.
KeywordsForced swim test Resident–intruder Olfactory bulbectomy Schedule-induced polydipsia 5-HT2C receptor agonist WAY-163909 Antidepressant Rapid onset
serotonin reuptake inhibitor
forced swim test
analysis of variance
standard error of the mean
differential reinforcement of low rate
least significant difference
The authors would like to thank Menelas Pangalos and Ron Magolda for their unwavering support of 5-HT2C agonist studies.
- Bickerdike MJ, Adams DR, Bentley J, Benwell KR, Cliffe IA, Kennett GA, Knight AR, Malcolm CS, Misra A, Quirk K, Roffey JRA, Dourish CT (2002) Radioligand binding profile and in vitro functional efficacy of VER-3323, a novel 5-HT2C/5-HT2B receptor agonist. 5th IUPHAR Satellite Meeting on SerotoninGoogle Scholar
- Bos M, Jenck F, Martin JR, Moreau JL, Sleight AJ, Wichmann J, Widmer U (1997) Novel agonists of 5HT2C receptors. Synthesis and biological evaluation of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines. Improved therapeutics for obsessive compulsive disorder. J Med Chem 15:2762–2769CrossRefGoogle Scholar
- Dunlop J, Sabb AL, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E, Sukoff S, Vogel R, Stack G, Schechter L, Harrison BL, Rosenzweig-Lipson S (2005) WAY-163909 (7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]-diazepino[6,7,1hi]indole); A novel 5-HT2C receptor selective agonist with anorectic activity. J Pharmacol Exp Ther 313(2):862–869PubMedCrossRefGoogle Scholar
- Dunlop J, Marquis M, Kim HL, Leung L, Kao J, Cheesman C, Rosenzweig-Lipson S (2006) Pharmacological profile of the 5-HT2C receptor agonist WAY-163909 ((7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole); therapeutic potential in multiple indications. CNS Drug Review 12:167–176CrossRefGoogle Scholar
- Freo U, Holloway HW, Greig NH, Soncrant TT (1992) Chronic treatment with meta-chlorophenylpiperazine (m-CPP) alters behavioral and cerebral metabolic responses to the serotonin agonists m-CPP and quipazine but not 8-hydroxy-2(di-N-propylamino)tetralin. Psychopharmacology 107:30–38PubMedCrossRefGoogle Scholar
- Leyson D, Kelder J (1998) Ligands for the 5-HT2C receptor as potential antidepressants and anxiolytics. In: van der Groot J (ed) Trends in drug research. Elsevier, Amsterdam, pp 49–61Google Scholar
- Marquis K, Sabb A, Logue SF, Stack G, Brennan JA, Piesla MJ, Comery TA, Grauer SM, Ashby CR, Nguyen HQ, Dawson LA, Stack G, Meltzer HY, Harrison BL, Rosenzweig-Lipson S (2007) WAY-163909 ((7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole): a novel 5-HT2C receptor selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320:486–496PubMedCrossRefGoogle Scholar
- McCall RB, Franklin SR, Hyslop DK, Knauer CS, Chio CL, Haber CL, Fitzgerald LW (2001) PNU-22394, a 5-HT2C receptor agonist, reduces feeding in rodents and produces weight loss in humans. Soc Neurosci Abstr 27:309.2Google Scholar
- Mitchell PJ, Redfern PH (2000) Effects of m-chlorophenylpiperazine and mesulergine on rodent agonistic behaviour. J Psychopharmacol 14:A32 (PD2)Google Scholar
- Redmond AM, McNamara MG, Dredge K, Kelly JP, Leondard BE (1997) Onset of action of venlafaxine, citalopram, and desipramine in the OB rat model of depression. J Psychopharmacol 11:A40Google Scholar
- Rosenzweig-Lipson S, Beyer C, Malberg J, Lin Q, Ashby CR, Graf R, Sung A, Grauer S, Logue S (2005) WAY-163909, a 5-HT2C selective agonist for the treatment of obesity, depression and schizophrenia: lack of tolerance. SFN Itinerary ViewerGoogle Scholar
- Sukoff Rizzo SJ, Schechter LE, Rosenzweig-Lipson S (2007) A novel approach for predicting antidepressant-induced sexual dysfunction in rats. Psychopharmacology, in pressGoogle Scholar
- Welmaker GS, Nelson JA, Sabalski JE, Sabb AL, Potoski JR, Graziano D, Kagan K, Coupet J, Dunlop J, Mazandarani H, Rosenzweig-Lipson S, Sukoff S, Zhang Y (2000) Synthesis and 5-Hydroxytryptamine (5-HT) activity of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines. Bioorg Med Chem Lett 10:1991–1994PubMedCrossRefGoogle Scholar