Rapid recovery of self-stimulation responding from depression by clozapine is prevented by the alpha 2-adrenoceptor agonist, clonidine.

Abstract

Typical and atypical antipsychotic agents were tested on rats responding for variable-interval electrical stimulation of the ventral tegmental area (VTA). The typical neuroleptics, chlorpromazine and haloperidol, led to prolonged depression of responding lasting at least 4 h, whereas response rates after similarly effective doses of the atypical agents, clozapine and risperidone, recovered to control levels in the same period. The role of alpha 2-adrenoceptors in producing these differences was investigated by administering clozapine together with an alpha 2-adrenoceptor agonist, clonidine, and chlorpromazine together with an alpha 2-adrenoceptor antagonist, idazoxan. The addition of clonidine extended the response-depressant activity of clozapine, resulting in prolonged depression comparable to that produced by chlorpromazine or haloperidol. Conversely, the addition of idazoxan to chlorpromazine shortened the duration of chlorpromazine's suppressant action to a level comparable to that of clozapine or risperidone. These results suggest that the brevity of clozapine's effects on operant behaviour (a feature which may be related to its reduced liability to extrapyramidal side-effects) may be a consequence of its alpha 2-adrenoceptor antagonist properties.