Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor.
Developing rats are far more sensitive than adults to the behavioral effects of haloperidol. The present results support the hypothesis that this change may reflect age-related changes in brain responses such as alterations in drug-receptor or drug-effector mechanisms. Dose-response studies of catalepsy and ptosis were conducted in male Sprague-Dawley rats aged 30, 56, or 100 days. Resulting dose-effect curves were approximately parallel and showed rightward shifts with highly significant progressive increases of ED50. Similar developmental decreases in drug sensitivity (3-6x) were found following systemic (PO or IP) administration of haloperidol or the phenothiazine neuroleptic perphenazine, which differ markedly in structure, potency, distribution, and metabolism. Age-related decreases in drug sensitivity (3-4x) were also found using intracerebroventricular (ICV) administration of both agents in an attempt to bypass potential "pharmacokinetic" influences. Since the age-dependent decrease in sensitivity to both neuroleptics was found during the rising phase of drug action (1st hour) and ranked: PO greater than IP greater than ICV, some change in absorption and distribution of both drugs may occur in addition to the apparently important maturational decrease in target-organ sensitivity indicated by the responses to direct ICV injection and by the similarity of results obtained with dissimilar agents.
D000284:Administration, Oral; D000375:Aging / Q000502:physiology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D005793:Generalization, Psychological / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D010546:Perphenazine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D014150:Antipsychotic Agents; D010546:Perphenazine; D006220:Haloperidol