Opposing effects of 5-HT(2A) and 5-HT(2C) receptor antagonists in the rat and mouse on premature responding in the five-choice serial reaction time test.
BACKGROUND
Serotonin (5-HT) has been linked to impulsivity with recent data suggesting that different receptor sub-types exert opposing influences on this behaviour.


OBJECTIVE
This work characterised the effects of 5-HT(2A) (ketanserin, (+/-)2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol] [M100907]), 5-HT(2B) (6-chloro-5-methyl-1-(5-quinolylcarbamoyl) indoline [SB215505]) and 5-HT(2C) (6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbomyl] indoline [SB242084]) receptor antagonists on impulsive behaviour, measured in the five-choice serial reaction time test (5CSRTT), in rats and mice. The effects of (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 (Ro60-0175), two compounds that have been used extensively as agonists for the 5-HT(2A) and 5-HT(2C) receptor, were also measured.


METHODS
Rats and mice were trained on the 5CSRTT in which reinforcement is earned for detecting and correctly responding to brief presentations of a stimulus light. Impulsivity in this task is measured as premature responding, before stimulus presentation. Several variants of the task were used in which the inter-trial interval (ITI) length was manipulated to alter basal levels of premature responding.


RESULTS
In the rat, ketanserin and M100907 reduced and SB242084 enhanced premature responding. SB215505 had no effect. DOI generally disrupted responding, while Ro60-0175 reduced premature responding when a long ITI was used. In mice, M100907 reduced and SB242084 increased premature responding when the ITI was lengthened. The effects of these drugs on other aspects of performance were less robust. M100907 and ketanserin did not affect response accuracy but tended to slow speed of responding; SB242084 occasionally increased speed of responding and slightly reduced accuracy.


CONCLUSIONS
Serotonin exerts both excitatory and inhibitory influences on motor impulsivity via 5-HT(2A) and 5-HT(2C) receptors in both rats and mice.
Section of Biopsychology, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. Paul_Fletcher@camh.net
Paul J
PJ
Fletcher
Maria
M
Tampakeras
Judy
J
Sinyard
Guy A
GA
Higgins
D000631:Aminopyridines / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D005021:Ethylamines / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D007175:Impulsive Behavior / Q000523:psychology*; D007211:Indoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012691:Serial Learning / Q000187:drug effects* / Q000502:physiology; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D013045:Species Specificity
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D000662:Amphetamines; D005021:Ethylamines; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; D011804:Quinolines; C103848:Ro 60-0175; C118948:SB 215505; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D007650:Ketanserin; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine