1. ¹Centre de recherche Fernand-Seguin, Hôpital Louis-H Lafontaine, Montréal, QC, Canada
2. ²Département de psychiatrie, Université de Montréal, Montréal, QC, Canada
3. ³Center for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

Correspondence: Dr P-P Rompré, Centre de recherche Fernand-Seguin, Hôpital Louis-H Lafontaine, 7331, Hochelaga, Montréal, QC, Canada H1N 3V2, Tel: +1 514 251 4015, Fax: +1 514 251 2617, E-mail: pierre-paul.rompre@umontreal.ca

Received 27 December 2005; Revised 5 April 2006; Accepted 16 May 2006; Published online 14 June 2006.

Abstract

Previous studies have shown that effective antipsychotic medications attenuate reward, an effect that is generally attributed to their effectiveness at blocking the dopamine D2-like receptors. As blockade of the serotonin type 2a (5-HT2a) receptors is a common property of the newer antipsychotics, the present study compared the effect of haloperidol, clozapine, and M100907 (a selective 5-HT2a antagonist) and the combined effect of haloperidol and M100907 treatment on brain stimulation reward (BSR). Experiments were performed on male Sprague–Dawley rats trained to produce an operant response to obtain electrical stimulation in the lateral hypothalamus. Measures of reward threshold were determined in different groups of rats using the curve-shift method using fixed current intensity and variable frequency before and at different times after injection of haloperidol (0.01, 0.05, 0.1, and 0.25 mg/kg), clozapine (1, 7.5, 15, and 30 mg/kg), M100907 (0.033, 0.1, and 0.3 mg/kg), or their vehicle. The effect of M100907 (0.3 mg/kg) on the attenuation of BSR by a sub- and suprathreshold dose of haloperidol was studied in another group of rats. Clozapine produced a dose-orderly increase in reward threshold with a mean maximal increase of 50%; at high doses, clozapine induced cessation of responding in several animals at different time periods. Haloperidol induced a dose-dependent increase in reward threshold, with the mean maximal increase (75%) being observed at the highest dose; it also produced a dose-dependent reduction of maximum rates of responding. M100907 failed to alter reward at any of the doses tested and had no effect on the subthreshold dose (0.01 mg/kg) of haloperidol. But when combined with a suprathreshold dose of haloperidol, M100907 reduced the reward-attenuating effect of haloperidol. These results show that 5-HT2a receptors are unlikely to constitute a component of the reward-relevant pathway activated by lateral hypothalamic stimulation. However, blockade of 5-HT2a receptors may account for the relatively lower level of reward attenuation produced by clozapine, and predict that antipsychotic medications that have a high affinity for the 5-HT2a receptor may be less likely to induce dysphoria.