Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety.
The 5-HT2C antagonist SB-242084 was examined in various anxiety tests at doses based on reversal of mCPP-induced hypoactivity (0.1--3 mg/kg ip). In the elevated plus-maze task, SB-242084 exhibited signs of anxiolysis (time spent, distance travelled, and entries into open arms), but this was potentially confounded by its general increase of locomotion; alprazolam selectively affected open-arm parameters. In a Geller--Seifter conflict test, SB-242084 produced a modest, nonsignificant increase in punished responding compared to the significant effect produced by diazepam. None of the treatments significantly affected unpunished responding. In the conditioned emotional response (CER) test, SB-242084 produced an increase in the suppression ratio (SR, smaller than diazepam). Since this 5-HT2C antagonist also increased lever pressing, an additional test was conducted with amphetamine that stimulated lever pressing but, nonetheless, failed to produce any change in SR. In the fear-potentiated startle task, SB-242084 was inactive in comparison to a significant effect of diazepam. The previously described reduction of schedule-induced polydipsia by fluoxetine and 5-HT2C receptor agonist Ro60-0175 was attenuated by SB-242084 pretreatment, however, the latter compound exhibited a potent increase in polydipsia when given alone. The present results demonstrate an anxiolytic potential of SB-242084, as well as an intrinsic response-enhancing property, however, both of these effects are task dependent.
Martin
James R
JR
Neuroscience Department, Pharma Division, F. Hoffmann-La Roche Ltd., CH-4070, Basel, Switzerland. james_r.martin@roche.com
Ballard
Theresa M
TM
Higgins
Guy A
GA
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000523:psychology*; D003192:Compulsive Behavior / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects; D003220:Conflict, Psychological; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004644:Emotions / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D018757:GABA Modulators / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects; D012055:Reinforcement Schedule; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013649:Taste / Q000187:drug effects
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D018757:GABA Modulators; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D003975:Diazepam