The ability of serotonin (5-HT)-selective compounds to reverse catalepsy due to blockade of dopamine (DA) receptors was examined in rats treated with the antipsychotic haloperidol (HAL). The 5-HT-releasing drug fenfluramine significantly reversed HAL-induced catalepsy. The 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin and buspirone potently and dose-dependently reversed HAL-induced catalepsy. The effect of 8-hydroxy-2-(di-n-propylamino)tetralin was blocked by pretreatment with the 5-HT1A/1B receptor antagonist pindolol, but not the 5-HT2 receptor antagonist ketanserin. The 5-HT1C/2 receptor agonist 2,5-dimethoxy-4-bromoamphetamine also completely reversed HAL-induced catalepsy, an effect blocked by ketanserin, but not pindolol. Neither antagonist alone had any effect. The 5-HT1B/1C receptor agonist trifluoromethylphenylpiperazine only partially reversed HAL-induced catalepsy, and the effect was not dose dependent. The 5-HT1C/2 receptor antagonist mianserin reversed HAL-induced catalepsy on its own; therefore, its ability to block the effect of trifluoromethylphenylpiperazine could not be tested. The nature of the disruption of HAL-induced catalepsy was examined by measuring the ability of increasing doses of HAL to surmount the effects of the serotonergic agonists. The mixed DA-D1/D2 receptor agonist apomorphine shifted the dose-effect curve for HAL to the right in a parallel manner, indicative of a competitive interaction between HAL and apomorphine at the D2 receptor. In contrast, the 5-HT receptor agonists flattened the dose-effect curve for HAL, suggestive of noncompetitive interactions. These data suggest that the 5-HT receptor agonists are not reversing HAL-induced catalepsy by indirectly increasing DA release. Rather, the agonists reverse HAL-induced catalepsy through interactions at their specific 5-HT receptor subtypes. Thus, the 5-HT receptor agonists may provide novel approaches for the development of drugs which can reverse or prevent the extrapyramidal side effects associated with antipsychotic treatment.