Ontogeny of tolerance to haloperidol: behavioral and biochemical measures.

Abstract

Developing and adult Sprague-Dawley rats were tested after acute or repeated haloperidol administration. Although 8-day-old rat pups showed a form of immobility in response to a single injection of haloperidol (1 mg/kg), 14-day-old rats did not show any behavioral response to the neuroleptic. By 21 days of age, an acute dose of haloperidol induced a cataleptic response similar to that described for adult animals. Following 7 days of repeated haloperidol administration, the cataleptogenic effects of haloperidol were attenuated in animals aged 21 days and older, but not in 8- and 14-day-old rats. Subjects were sacrificed 70 min after the injection of the test dose of haloperidol or saline and the corpus striatum and olfactory tubercles were dissected for HPLC determination of dopamine (DA) and its metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In the corpus striatum, an area believed to be important for DA-related catalepsy, acute and repeated haloperidol induced a slight increase in concentrations of HVA in 8-day-old rats, and an increase in both DOPAC and HVA concentrations in animals aged 14 days and older. Tolerance after repeated haloperidol administration, in the form of an attenuation of the haloperidol-induced increase in DA metabolites, was not apparent until 35 days of age. These data contrast with the behavioral data, which indicate that the ability to develop a tolerance to the cataleptogenic effects of haloperidol matures by 21 days of age. The pattern of responses in the olfactory tubercles differed from those observed in the striatum. Following acute haloperidol, subjects did not show any increase in HVA until 14 days of age, and in both HVA and DOPAC until 21 days of age. At no age, including adults, was one week of repeated administration of haloperidol sufficient to induce tolerance to the effects of haloperidol on DA metabolites in the olfactory tubercles. In addition to providing information about the development of certain aspects of DA systems in rats, these studies suggest that an attenuation of the haloperidol-induced increase in DA metabolites is not necessary for the development of tolerance to haloperidol-induced catalepsy.