Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents.
BACKGROUND
Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs.


OBJECTIVE
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.


RESULTS
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-HT(2C/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.


CONCLUSIONS
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.
Rosenzweig-Lipson
Sharon
S
Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA. rosenzs@wyeth.com
Sabb
Annmarie
A
Stack
Gary
G
Mitchell
Paul
P
Lucki
Irwin
I
Malberg
Jessica E
JE
Grauer
Steve
S
Brennan
Julie
J
Cryan
John F
JF
Sukoff Rizzo
Stacey J
SJ
Dunlop
John
J
Barrett
James E
JE
Marquis
Karen L
KL
D000374:Aggression / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001381:Azepines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009771:Obsessive-Compulsive Disorder / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D011921:Rats, Inbred WKY; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012726:Sexual Behavior, Animal / Q000187:drug effects; D012735:Sexual Dysfunction, Physiological / Q000139:chemically induced; D013550:Swimming
C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D000928:Antidepressive Agents; D001381:Azepines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D017366:Serotonin Receptor Agonists