Effects of quipazine and m-chlorophenylbiguanide (m-CPBG) on temporal differentiation:: evidence for the involvement of 5-HT2A but not 5-HT3 receptors in interval timing behaviour

Rationale: Temporal differentiation refers to animals' ability to regulate their behaviour during an ongoing interval. Striatal dopaminergic mechanisms are purported to be involved in temporal differentiation, and recent evidence also implicates 5-hydroxytryptaminergic (5-HTergic) mechanisms, possibly mediated by 5-HT(2)A receptors. There is evidence that 5-HT3 receptors contribute to the regulation of dopamine release in the basal ganglia; however, it is not known whether 5-HT3 receptor stimulation can influence temporal differentiation. Objective: We examined the effects of a selective 5-HT3 receptor agonist m-CPBG, a mixed 5-HT2A/3 receptor agonist quipazine, and selective 5-HT3 and 5-HT2A receptor antagonists (MDL72222 and ketanserin, respectively) on temporal differentiation in a free-operant psychophysical procedure. Methods: Twenty-four rats were trained to respond on two levers (A and 13) under a free-operant psychophysical schedule, in which sucrose reinforcement (0.6 M, 50 mu l) was provided intermittently for responding on A during the first half and on, B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data [percent responding on B (%B) vs time from trial onset (t)], and quantitative indices of timing performance [T50 (value of t corresponding to %B=50), Weber fraction, and mean time of switching from A:to B, S-50] were derived. Results: Quipazine (0.5, 1, and 2 mg kg(-1)) altered timing performance, dose-dependently reducing T50 and S50; m-CPBG (2.5, 5, and 10 mg kg(-1)) had no significant effect. The effect of quipazine was antagonized by ketanserin (2 mg kg(-1)), but not by MDL-72222 (1mg kg(-1)). Conclusions: the present results provide no evidence for the involvement of 5HT(3) receptors in temporal differentiation and indicate that the effect of quipazine on performance was mediated by 5-HT2A receptor stimulation. The results are consistent with previous evidence for the involvement of 5-HT2A receptors in interval timing behaviour.