Low-dose adolescent nicotine and methylphenidate have additive effects on adult behavior and neurochemistry

Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) have higher rates of smoking than adolescents without ADHD. Since methylphenidate is the primary drug used to treat ADHD, it is likely that many adolescents are exposed to both methylphenidate and nicotine. Recent studies have established that adolescent nicotine induces long-term changes in several neurobehavioral variables. Limited data also suggest that adolescent methylphenidate may affect neural development. Nicotine tolerance is a well-established behavioral phenomenon in rodents, yet the underlying mechanism remains elusive. Recent theories suggest that changes in ventral striatal dopamine indices may relate to nicotine tolerance. As an initial determination of whether nicotine and methylphenidate have additive effects on neurobehavioral development, the present study investigated the combined effects of adolescent nicotine [2 mg/kg/d] alone or in conjunction with methylphenidate [1.5 mg/kg, 2 × daily] following a one-month drug free period on adult behavioral tolerance to nicotine [0.5 mg/kg s.c.] and its relation to dopamine receptor mRNA expression in the ventral striatum. Animals with chronic combined (nicotine + methylphenidate) adolescent exposure displayed stronger tolerance as adults to the nicotine-induced locomotor effects in comparison to animals with adolescent exposure to nicotine alone, methylphenidate alone, or controls. Combined chronic adolescent exposure significantly elevated adult D3nf mRNA expression levels in the nucleus accumbens, however a single nicotine injection in adults increased D3nf mRNA levels in naïve animals and decreased D3nf mRNA levels in those that had been previously exposed to combined stimulants during adolescence. Conversely, a single adult nicotine injection increased D1 mRNA levels in the adult nucleus accumbens, particularly in the shell, but only in rats previously exposed to nicotine or methylphenidate as adolescents. To our knowledge this is the first study that has shown long-term behavioral and neurochemical changes stemming from low chronic exposure of these two commonly co-consumed stimulants during adolescence.

► We investigated long-term effects of adolescent stimulant exposure.
► Nicotine and methylphenidate have an additive effect on behavioral tolerance.
► Adult mRNA expression was differentially altered due to adolescent exposure.
► Some neurochemical changes are seen only after adult stimulant exposure.
► The splice variant D3nf appears to have a role in the development of tolerance.