RationaleNicotine and alcohol each can serve as the gateway to other drugs.ObjectiveThe current study was sought to determine if prior nicotine and alcohol exposure alters amphetamine reward and if age and dopaminergic neurotransmission are involved.MethodsMale and female adolescent and adult C57BL/6J mice were tested for baseline place preference, received six conditioning with saline/nicotine (0.25 mg/kg) twice daily followed by six conditioning with saline/ethanol (2 g/kg) in a counterbalance manner. Control mice were conditioned with saline/saline throughout. Finally, mice were conditioned with amphetamine (3 mg/kg) once in the nicotine-alcohol-paired chamber and then tested for CPP 24 h later. The following day, mice were challenged with amphetamine (1 mg/kg) and tested for CPP under a drugged state. Mice were then immediately euthanized, brain removed and nucleus accumbens isolated and processed for the expression of dopamine receptors and transporter, and glutamate receptors.ResultsWe observed a greater amphetamine-induced CPP in adolescent than adult mice but no change in state-dependent CPP between the two age groups. In contrast, amphetamine-induced CPP in mice with prior nicotine-alcohol exposure was greater in adult than adolescent mice under both drug-free and drugged states. The enhanced response in adult mice was associated with greater expression of dopamine-transporter, reduced D2 receptors, and increased D1 receptors with no changes in glutamate receptors.ConclusionsThese results suggest that prior nicotine and alcohol exposure differentially alters the rewarding action of amphetamine in adult and adolescent mice and alterations in dopaminergic neurotransmission may be involved in this phenotype.