Early postnatal cocaine exposure causes sequential, dose-dependent, enduring but reversible supersensitivity in 5-HT 2A receptor-mediated function during development in male mice

Abstract

This report investigated whether postnatal exposure to cocaine affects the index of 5-HT 2A receptor function during development by utilizing the ability of the 5-HT 2A/C agonist DOI to induce the head-twitch response (HTR) in mice. Thus, several groups of mice litters were treated with varying doses of cocaine (0, 0.5, 1, 5, and 10 mg/kg, IP) twice daily from postnatal days 5 to 14. Then, different groups of cocaine-exposed male mice pups along with their corresponding age-matched vehicle-exposed control groups were HTR tested once during development on the following postnatal test days: 15, 16, 18, 20, 30, 45, and 60. The HTR testing involved administration of DOI (0.5 mg/kg, IP) and counting the frequency of the behavior for the next 20 min. Cocaine exposure caused bell-shaped, dose-dependent, enduring but reversible increase in DOI-induced HTR frequency (mean ± SEM) during development. The developing pups were most sensitive to low and intermediate doses of cocaine (0.5–5 mg/kg). The greatest degree of increase in HTR frequency in response to DOI challenge occurred in the 1 mg/kg cocaine-exposure group on most test days. The onset of HTR supersensitivity varied from 48 h (5 mg/kg) to 144 h (0.5 mg/kg) following the termination of chronic cocaine exposure. Moreover, maximal supersensitivity for the latter doses of cocaine occurred 96 and 384 h postcocaine treatment, respectively. Other cocaine exposure groups attained their maxima sometime between the latter time periods. The duration of persistence of 5-HT 2A receptor supersensitivity varied with different doses of cocaine: the 10-mg/kg group was supersensitive up to 384 h postcocaine treatment, the 1- and 5-mg/kg groups up to 744 h; and the 0.5-mg/kg group up to 1104 h. Although developmentally cocaine-exposed pups exhibit some similarities (i.e., exquisite sensitivity and bell-shaped dose–response) in 5-HT 2A receptor adaptation to mature adult mice exposed to cocaine, they also differ from mature adult cocaine-exposed mice in the onset of appearance as well as the enduring persistence of the induced supersensitivity.