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

Abstract

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.

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Acknowledgements

We thank Danielle E. Humphrey for help with injecting the rats, and Christopher P. Plant for help with the assays. We also thank Nancy R. Zahniser and Gaynor A. Larson for their assistance in setting up the cocaine assay.

Funding

This research was supported by NIGMS training grant GM083883 (MGA and ATQ) and NIDA training grant DA033877 (AMY).

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Correspondence to Sanders A. McDougall.

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McDougall, S.A., Apodaca, M.G., Mohd-Yusof, A. et al. Ontogeny of cocaine-induced behaviors and cocaine pharmacokinetics in male and female neonatal, preweanling, and adult rats. Psychopharmacology 235, 1967–1980 (2018). https://doi.org/10.1007/s00213-018-4894-8

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Keywords

  • Cocaine
  • Behavior
  • Ontogeny
  • Pharmacokinetics
  • Half-life