Safety pharmacology assessment of central nervous system function in juvenile and adult rats: Effects of pharmacological reference compounds

IntroductionRecent EU/US pediatric legislation and FDA/EMEA guidelines recognize the potential differences in safety profiles of drugs in adults versus young patients. Hence safety studies are recommended to investigate key functional domains of e.g. the developing CNS. Methods: Selected psychoactive stimulants (caffeine, d-amphetamine, scopolamine) and depressants (baclofen, diazepam, haloperidol, chlorpromazine, imipramine, morphine) were characterized upon single administration with regard to behavioural parameters, locomotor activity, body temperature, pro-/anti-convulsive activity (pentylenetetrazole, PTZ), and nocifensive responses (hotplate) in neonatal (2 weeks), juvenile (4 weeks) and adult rats (8–9 weeks). Results: In vehicle-treated rats, behavioural patterns matured with age, locomotor activity and handling-induced rise in body temperature were enhanced, whereas PTZ convulsion threshold dose and nocifensive response latency decreased. Single test compound treatment elicited behavioural effects characteristic for psychoactive drugs with stimulating and depressing properties regardless of age. However, incidence of certain behaviours, and magnitude of effects on locomotor activity and body temperature varied with age and became generally more pronounced in adult rats. Pro-/anti-convulsive effects and delayed nocifensive responses did not differ between juvenile and adult rats. Conclusion: CNS effects of selected psychoactive reference compounds were qualitatively similar, but quantitatively different in neonatal, juvenile and adult rats.