Early postnatal cocaine exposure causes sequential, dose-dependent, enduring but reversible supersensitivity in 5-HT2A receptor-mediated function during development in male mice.
This report investigated whether postnatal exposure to cocaine affects the index of 5-HT2A receptor function during development by utilizing the ability of the 5-HT2A/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-HT2A 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-HT2A 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.
Darmani
N A
NA
Department of Pharmacology, Kirksville College of Osteopathic Medicine, MO 63501, USA. ndarmani@kcom.edu
Ahmad
B
B
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology*
D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D003042:Cocaine