Nicotine and methylphenidate on adolescent brain development and addiction liability: Dose investigation

The present study investigated the combined effects of chronic adolescent nicotine and methylphenidate on behavioral tolerance to these drugs in adulthood and how they relate to glutamate and dopamine receptor mRNA expression in the medial prefrontal cortex and striatum. Adolescent rats [P28] received low dose nicotine (2 mg/kg per day) through subcutaneously implanted osmotic pumps. Subsequently [P35] low dose methylphenidate (1.5 mg/kg) was administered orally (twice daily 5 days per week) and both drugs continued until the end of adolescence [P56]. Following a one-month drug free period all animals were challenged with either a stimulant (nicotine, 0.5 mg/kg) or saline in the open field. Twenty-four hours following testing animals were sacrificed and mRNAs of the dopamine [D1, D2, D3, D3nf splice variant] and glutamate N-methyl-D-aspartic acid [NR2a and NR2b subunits] receptors were examined. Animals with combined exposure displayed stronger tolerance to the stimulant challenge compared to single drug exposure or control groups indicating that combined consumption has an additive effect. This additive relationship persisted in mRNA expression of various dopamine and glutamate receptor indices. Many of these neurochemical changes were only revealed following the single adult stimulant exposure. Adolescent stimulant exposure resulted in long-term changes in mRNAs of the NR2b subunit as well as D1, D2 and D3nf expression in many brain regions we investigated. These changes are possibly related to addiction liability but unrelated to behavioral tolerance. To our knowledge this is the first study that has shown long-term behavioral and neurochemical changes stemming from very low chronic exposure of these two commonly co-consumed stimulants during adolescence.