Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of reward.
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.
Benaliouad
Faïza
F
Centre de recherche Fernand-Seguin, Hôpital Louis-H Lafontaine, Montréal, QC, Canada.
Kapur
Shitij
S
Rompré
Pierre-Paul
PP
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D004056:Differential Threshold / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005108:Extinction, Psychological / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D012646:Self Administration; D058830:Serotonin 5-HT2 Receptor Antagonists
D018492:Dopamine Antagonists; D005464:Fluorobenzenes; D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists; C079049:volinanserin; D003024:Clozapine; D006220:Haloperidol