Ontogeny of cocaine-induced behaviors and cocaine pharmacokinetics in male and female neonatal, preweanling, and adult rats.

RATIONALE: Ontogenetic differences in the behavioral responsiveness to cocaine have often been attributed to the maturation of dopaminergic elements (e.g., dopamine transporters, D2High receptors, receptor coupling, etc.). OBJECTIVE: The purpose of this study was to determine whether ontogenetic changes in cocaine pharmacokinetics might contribute to age-dependent differences in behavioral responsiveness. METHODS: Male and female neonatal (PD 5), preweanling (PD 10 and PD 20), and adult (PD 70) rats were injected (IP) with cocaine or saline and various behaviors (e.g., locomotor activity, forelimb paddle, vertical activity, head-down sniffing, etc.) were measured for 90 min. In a separate experiment, the dorsal striata of young and adult rats were removed at 10 time points (0-210 min) after IP cocaine administration. Peak cocaine values, cocaine half-life, and dopamine levels were determined using HPLC. RESULTS: When converted to percent of saline controls, PD 5 and PD 10 rats were generally more sensitive to cocaine than older rats, but this effect varied according to the behavior being assessed. Peak cocaine values did not differ according to age or sex, but cocaine half-life in brain was approximately 2 times longer in PD 5 and PD 10 rats than adults. Cocaine pharmacokinetics did not differ between PD 20 and PD 70 rats. CONCLUSIONS: Differences in the cocaine-induced behavioral responsiveness of very young rats (PD 5 and PD 10) and adults may be attributable, at least in part, to pharmacokinetic factors; whereas, age-dependent behavioral differences between the late preweanling period and adulthood cannot readily be ascribed to cocaine pharmacokinetics.

Early ontogeny of D-amphetamine-induced one-trial behavioral sensitization.

The early ontogeny of D-amphetamine-induced one-trial behavioral sensitization was characterized using male and female preweanling and preadolescent rats. In Experiment 1, rats were injected with saline or D-amphetamine (1, 4, or 8mg/kg) in activity chambers or the home cage on postnatal day (PD) 12, PD 16, PD 20, or PD 24. One day later, rats were challenged with either 0.5 or 2mg/kg D-amphetamine and distance traveled was measured in activity chambers for 120min. In Experiment 2, saline or D-amphetamine was administered in activity chambers on PD 24, while a challenge injection of D-amphetamine (0.25-4mg/kg) was given on PD 25. At younger ages (PD 13 and PD 17), a strong sensitized response was evident on the test day regardless of whether rats were pretreated with D-amphetamine (4 or 8mg/kg) before being placed in the activity chamber or 30min after being returned to the home cage. Rats did not display D-amphetamine-induced behavioral sensitization on PD 21, nor was context-dependent sensitization apparent on PD 25 even when a broad dose range of D-amphetamine was used. When low doses of D-amphetamine were administered on the pretreatment and test days (1 and 0.5mg/kg, respectively), sensitized responding was not evident at any age. In summary, D-amphetamine-induced one-trial behavioral sensitization was only apparent within a narrow developmental window during early ontogeny. This ontogenetic pattern of sensitized responding is similar to the one produced by methamphetamine and distinct from the pattern produced by cocaine. The unique sensitization profiles resulting from repeated D-amphetamine and cocaine treatment may be a consequence of their different mechanisms of action.