Repeated haloperidol administration changes basal release of striatal dopamine and subsequent response to haloperidol challenge

The effects of acute or repeated administration of haloperidol on release of dopamine (DA) and homovanillic acid (HVA) from striata of awake rats were studied using a microdialysis probe. A single injection of haloperidol (1 mg/kg, i.p.) produced a time-dependent increase in DA and HVA in the perfusate. Comparative studies in rats anesthetized with 300 mg/kg of chloral hydrate given i.p. found that anesthesia decreased the basal release of DA, but not HVA, and significantly blocked haloperidol-induced increases in DA, while haloperidol-induced increases in HVA were not affected. Studies done in awake rats found that 21 repeated daily injections of haloperidol increased the basal release of DA, but not HVA. Subsequent challenge with haloperidol indicated a significant decrease in responsiveness to haloperidol-induced release of DA, but not HVA, in chronically dosed rats. These data suggest that repeated exposure to haloperidol causes a compensatory increase in extracellular DA release. That these compensatory changes may be associated with the increased therapeutic efficacy or extrapyramidal side effects of neuroleptics following repeated dosing warrants further study.