Cyclin-Dependent Kinase Inhibitor 1a (p21) Modulates Response to Cocaine and Motivated Behaviors

Abstract

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 2/2 mice, whereas cocaine-induced place preference was enhanced. Interestingly, k-opioid-induced place aversion was also significantly enhanced. Concentrationdependent analysis of locomotor activity in response to cocaine demonstrated a rightward shift in the p21 2/2 mice. Pretreatment with a 5-hydroxytryptamine receptor antagonist did not alter the enhancement of cocaine-induced conditioned place preference in p21 2/2 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 2/2 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.

Lipidomic changes in the rat hippocampus following cocaine conditioning, extinction, and reinstatement of drug‐seeking

“…We modified a behavioral model based on that described in previous studies (Scholpa et al, ; Seymour & Wagner, ) that incorporated extinction, reinstatement, and prolonged abstinence in order to model a pattern of relapse representative of what might be observed in humans that use cocaine (Figure a). Cocaine‐treated rats exhibited place preference following conditioning as indicated by more time spent in the designated drug‐paired compartment during the CPP post‐test than during the pretest (Figure b).…”

“…Behavioral testing took place in 43.2‐cm × 43.2‐cm chambers with clear plastic walls and a smooth solid floor (Med Associates Inc.), as described previously (Scholpa, Briggs, Wagner, & Cummings, ). Briefly, each chamber was located in a sound‐attenuating box equipped with two house lights, ventilation fan, and photo beam banks for horizontal activity detection.…”

“…Region‐specific brain and liver tissues were extracted 7 days after the final exposure to cocaine, as described previously (Scholpa et al, ). Briefly, animals were anesthetized with halothane prior to decapitation in compliance with protocols approved by the University of Georgia Animal Care and Use guidelines.…”

“…Behavioral testing took place in 43.2-cm × 43.2-cm chambers with clear plastic walls and a smooth solid floor (Med Associates Inc.), as described previously (Scholpa, Briggs, Wagner, & Cummings, 2016…”

Nephrotoxicity of epigenetic inhibitors used for the treatment of cancer

“…While not wanting to repeat the above studies, we still wished to validate the activity of these inhibitors in these cell lines. Thus, we assessed changes in a specific gene whose expression we recently demonstrated to be mediated by both methylation and histone acetylation, namely p21 [40, 41]. Further, we, along with others, have also shown p21 to be an important mediator of renal toxicity [42–44].…”