Development and persistence of long-lasting behavioral sensitization to cocaine in female mice: role of the nNOS gene.

Our recent studies have shown that the neuronal nitric oxide synthase (nNOS) gene is required for the development and persistence of psychomotor sensitization to cocaine in adult but not adolescent male mice (Balda, M.A., Anderson, K.L., Itzhak, Y., 2008. Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice. Psychopharmacology (Berlin) 200, 509-519.). The aim of the present study was to investigate the contribution of the nNOS gene to cocaine-induced behavioral sensitization in adolescent and adult female mice. Adolescent and adult wild type (WT) and nNOS knockout (KO) mice received saline or cocaine (20 mg/kg) for 5 days and then were challenged with cocaine (20 mg/kg) after a drug-free period of either 10, 30, or 90 days. Context-dependent sensitization was determined by measuring saline-induced locomotor activity in the previously cocaine-paired environment. Results show that adolescent females of both genotypes, like their adult counterparts, developed long-lasting behavioral sensitization to cocaine (a three-month period), suggesting high vulnerability of females to cocaine regardless of age. An effect of genotype was observed in the initiation of sensitization, e.g., delayed onset in the absence of the nNOS gene. The only age-dependent difference observed was that adult, but not adolescent mice developed context-dependent sensitization. The present study suggests that long-term expression of cocaine-induced behavioral sensitization in females (adolescent and adult) is nNOS-independent, unlike our previous findings in adult males.