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Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor
A Campbell1, R J Baldessarini, M H Teicher
1Department of Psychiatry, Harvard Medical School, Belmont, MA.
Psychopharmacology
|January 1, 1988
Summary
Young rats show higher sensitivity to haloperidol and perphenazine neuroleptics than adult rats. This age-related decrease in drug sensitivity is linked to brain maturation, affecting drug-receptor interactions.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Developing animals exhibit heightened sensitivity to neuroleptic drugs compared to adults.
- This sensitivity difference suggests age-related changes in brain mechanisms, potentially involving drug-receptor interactions or effector systems.
Purpose of the Study:
- To investigate age-related changes in sensitivity to neuroleptic drugs in developing rats.
- To explore the role of pharmacokinetic versus target-organ sensitivity in developmental differences in drug response.
Main Methods:
- Dose-response studies of catalepsy and ptosis were performed in male Sprague-Dawley rats at 30, 56, and 100 days of age.
- Haloperidol and perphenazine were administered via oral (PO), intraperitoneal (IP), and intracerebroventricular (ICV) routes to assess drug sensitivity.
- ED50 values were calculated to quantify drug potency and shifts in dose-effect curves.
Main Results:
- Significant, progressive increases in ED50 (decreased sensitivity) were observed with age for both haloperidol and perphenazine.
- Systemic administration showed a 3-6 fold decrease in sensitivity, while ICV administration revealed a 3-4 fold decrease, indicating both pharmacokinetic and target-organ contributions.
- The age-dependent decrease in sensitivity was more pronounced with PO and IP administration compared to ICV, suggesting absorption and distribution play a role.
Conclusions:
- Developing rats are significantly more sensitive to the behavioral effects of haloperidol and perphenazine than adult rats.
- Maturation of the central nervous system leads to decreased sensitivity to neuroleptics, impacting drug-receptor or drug-effector mechanisms.
- Both altered pharmacokinetics (absorption, distribution) and reduced target-organ sensitivity contribute to the observed age-related differences in neuroleptic drug effects.