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Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum

Abstract

Dopamine is vital for coordinated motion and for association learning linked to behavioral reinforcement. Here we show that the precise overlap of striatal dopaminergic and cholinergic fibers underlies potent control of dopamine release by ongoing nicotinic receptor activity. In mouse striatal slices, nicotinic antagonists or depletion of endogenous acetylcholine decreased evoked dopamine release by 90%. Nicotine at the concentration experienced by smokers also regulated dopamine release. In mutant mice lacking the β2 nicotinic subunit, evoked dopamine release was dramatically suppressed, and those mice did not show cholinergic regulation of dopamine release. The results offer new perspectives when considering nicotine addiction and the high prevalence of smoking in schizophrenics.

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Figure 1: Dense and overlapping distribution of ACh and dopamine in the striatum.
Figure 2: Inhibition of ACh vesicular transport by vesamicol reduces dopamine release in the striatum.
Figure 3: Nicotinic but not muscarinic ACh receptors regulate dopamine release in the striatum.
Figure 4: Bath-applied nicotine reduces action-potential-dependent dopamine release.
Figure 5: An AChE inhibitor, ambenonium, reduces dopamine release in the striatum.
Figure 6: A specific inhibitor of β2* nAChRs, DHβE, potently reduces evoked dopamine release.
Figure 7: β2-null mice have decreased dopamine release, and the release is not regulated by DHβE or nicotine.

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Acknowledgements

We thank A. Beaudet and A. Orr-Urtreger for providing the mutant mice, and Y. Schmitz and D. Sulzer for advice with the techniques. The work was supported by the National Institute on Drug Abuse (DA09411 and DA12661), the National Institute of Neurological Disorders and Stroke (NS21229) and the NARSAD (to F.M.Z.).

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Correspondence to John A. Dani.

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Zhou, FM., Liang, Y. & Dani, J. Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat Neurosci 4, 1224–1229 (2001). https://doi.org/10.1038/nn769

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