This study investigated the functional role of cyclin-dependent kinase inhibitor 1a (Cdkn1a or p21) in cocaine-induced responses using a knockout mouse model. Acute locomotor activity after cocaine administration (15 mg/kg, i.p.) was decreased in p21−/− mice, whereas cocaine-induced place preference was enhanced. Interestingly, κ-opioid–induced place aversion was also significantly enhanced. Concentration-dependent analysis of locomotor activity in response to cocaine demonstrated a rightward shift in the p21−/− mice. Pretreatment with a 5-hydroxytryptamine receptor antagonist did not alter the enhancement of cocaine-induced conditioned place preference in p21−/− mice, indicating a lack of involvement of serotonergic signaling in this response. Cocaine exposure increased p21 expression exclusively in the ventral sector of the hippocampus of rodents after either contingent or noncontingent drug administration. Increased p21 expression was accompanied by increased histone acetylation of the p21 promoter region in rats. Finally, increased neurogenesis in the dorsal hippocampus of p21−/− mice was also observed. These results show that functional loss of p21 altered the acute locomotor response to cocaine and the conditioned responses to either rewarding or aversive stimuli. Collectively, these findings demonstrate a previously unreported involvement of p21 in modulating responses to cocaine and in motivated behaviors.
- Received November 20, 2015.
- Accepted January 19, 2016.
This research was supported by the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering [Grants EB08153 and EB0116100 (to B.S.C.)]; the National Institutes of Health National Institute on Drug Abuse [Grant DA016302 (to J.J.W.)]; the Achievement Rewards for College Scientists Foundation; the Alfred P. Sloan Foundation [Sloan Graduate Minority Fellowship]; and the Interdisciplinary Toxicology Program [Graduate Stipend (to N.E.S.)].
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics