Serotonergic involvement in haloperidol-induced catalepsy.
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.
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia.
B S
BS
Neal-Beliveau
J N
JN
Joyce
I
I
Lucki
D000818:Animals; D002375:Catalepsy / Q000139:chemically induced*; D006220:Haloperidol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists; D009435:Synaptic Transmission / Q000187:drug effects
D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D006220:Haloperidol