5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion.
BACKGROUND
Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT(2A) receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT(2A) and 5-HT(2C) receptors have opposing effects on behaviour, and that the 5-HT(2C) receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion.


OBJECTIVE
To assess the effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents.


METHODS
The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats. RESULTS. ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls.


CONCLUSIONS
These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT(2) receptor family is functionally heterogeneous. Although both 5-HT(2A) and 5-HT(2C) receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.
Winstanley
Catharine A
CA
Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK. caw42@cam.ac.uk
Theobald
David E H
DE
Dalley
Jeffrey W
JW
Glennon
Jeffrey C
JC
Robbins
Trevor W
TW
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology; D007175:Impulsive Behavior / Q000188:drug therapy* / Q000523:psychology*; D007211:Indoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; C079049:volinanserin