α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

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Abstract
Modulation of striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Nicotine, by desensitizing β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) on striatal DA axons, significantly enhances how DA is released by reward-related burst activity compared to nonreward-related tonic activity. This action provides a synaptic mechanism for nicotine to facilitate the DA-dependent reinforcement. The subfamily of β2*-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of α6β2*-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real-time using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in mouse striatal slices. The α6-specific antagonist α-conotoxin-MII suppressed DA release evoked by single and low-frequency action potentials and concurrently enhanced release by high-frequency bursts in a manner similar to the β2*-selective antagonist dihydro-β-erythroidine (DHβE) in NAc, but less so in CPu. The greater role for α6*-nAChRs in NAc was not due to any confounding regional difference in ACh tone since elevated ACh levels (after the acetylcholinesterase inhibitor ambenonium) had similar outcomes in NAc and CPu. Rather, there appear to be underlying differences in nAChR subtype function in NAc and CPu. In summary, we reveal that α6β2*-nAChRs dominate the effects of nicotine on DA release in NAc, whereas in CPu their role is minor alongside other β2*-nAChRs (eg α4*), These data offer new insights to suggest striatal α6*-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.