Circadian changes in behavioral effects of haloperidol in rats

Circadian changes in behavioral responses to haloperidol were evaluated in rats under normal and altered lighting cycles. There was a 5.5-fold change in ED50 between the maximum (4 PM) and minimum (4 AM) cataleptic response to the drug under normal lighting (lights of 7 AM- 7 PM). The rhythm was present whether the same rats were tested repeatedly, or fresh rats were used at each time to avoid drug effects which persist for at least several days. Under normal lighting, the maximum cataleptic effect of haloperidol corresponded closely to the light-phase minimum of spontaneous motor activity in untreated rats. Measures of sedation (ptosis and motor inhibition) induced by haloperidol yielded small circadian rhythms under normal lighting and were highly dependent on the baseline level of arousal. A month of constant light or dark, or reversed dark-light cycles had small effects on the sedative actions of haloperidol, although inhibition of locomotion tended to phase-shift with general arousal; these changes did not alter the catalepsy rhythm. While the circadian rhythm of spontaneous activity underwent a complete reversal within 1 month (t 1/2 =17 days) of reversed lighting cycles, the catalepsy rhythm changed very gradually (t 1/2 = 82 days) and required nearly 6 months for complete reversal. Thus, catalepsy is a robust endogenously regulated circadian response that is only slowly influenced by altered lighting conditions which dissociate this rhythm of neuroleptic response from that of spontaneous general arousal. Endogenous neurobiologic and pharmacokinetic factors may contribute to circadian changes in neuroleptic responses.