The role of monoamine neurotransmitter systems in the nicotine discriminative stimulus

Nicotine serves as a reinforcer and induces a robust discriminative stimulus which is primarily mediated by neuronal nicotinic receptors. As a secondary effect of nicotinic stimulation, nicotine elicits an enhanced release of the biogenic amine neurotransmitters dopamine, norepinephrine and serotonin. In particular, compounds with dopaminergic activity have been reported to modify both the reinforcing and discriminative stimulus properties of nicotine. The present study examined a number of dopaminergic, noradrenergic and serotonergic compounds for their effectiveness in reproducing or modifying the stimulus properties of nicotine in rats. The non-selective dopamine agonists amphetamine, cocaine and apomorphine produced partial substitution for nicotine, while the selective D2/D3 agonists bromocriptine and 7-OH-DPAT and the dopamine autoreceptor antagonist (+)-AJ-76 had little effect. The substitution of amphetamine for nicotine was not blocked by haloperidol, suggesting a minimal role for D2 receptors in the nicotine-like discriminative effects of stimulants. The selective D1 agonist SKF 81,297 produced partial substitution for nicotine (45% maximum), but further experiments with the D1 antagonist SCH 23,390 and with rats trained in a three-way discrimination procedure failed to support a primary role for this receptor in the substitution of dopaminergic drugs for nicotine. Finally, tests of compounds with effects on noradrenergic or serotonergic neurotransmission did not yield strong evidence for the involvement of these systems. Taken together, these data support earlier suggestions that activation of dopamine receptor subtypes plays a role in the nicotine-like stimulus properties of abused stimulants, but do not clearly identify a single subtype that is uniquely responsible.