Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice

Rationale: Previous studies have suggested the involvement of neuronal nitric oxide synthase (nNOS) in the development of sensitization to psychostimulants. Ontogeny-dependent differences in the response to psychostimulants have been reported. Objective: The objectives were to investigate (a) the short- and long-term consequences of adolescent and adult cocaine exposure on behavioral sensitization and (b) the role of the nNOS gene in behavioral sensitization in adolescent and adult mice. Materials and methods: 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 10 or 30 days. Locomotor activity was recorded by infrared beam interruptions. nNOS immunoreactive (ir) neurons in the dorsal and ventral striatum were quantified 24 h after repeated administration of cocaine to adolescent and adult WT mice. Results: Repeated administration of cocaine to either WT or nNOS KO mice during adolescence resulted in locomotor sensitization, which persisted into adulthood. WT but not KO adult mice developed long-term sensitization to cocaine. Repeated cocaine administration resulted in a 96% increase in the expression of nNOS-ir neurons in the dorsal striatum of adult but not adolescent WT mice. Conclusions: The nNOS gene is essential for the induction of behavioral sensitization to cocaine in adulthood but not in adolescence. The increased expression of nNOS-ir neurons in the dorsal striatum may underlie the induction of behavioral sensitization in adulthood. Thus, the NO-signaling pathway has an ontogeny-dependent role in the neuroplasticity underlying cocaine behavioral sensitization.