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The Journal of Neuroscience, December 15, 2004, 24(50):11328-11336; doi:10.1523/JNEUROSCI.1559-04.2004

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Cellular/Molecular
Nicotine Enhancement of Dopamine Release by a Calcium-Dependent Increase in the Size of the Readily Releasable Pool of Synaptic Vesicles

Timothy J. Turner

Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111

A major factor underlying compulsive tobacco use is nicotine-induced modulation of dopamine release in the mesolimbic reward pathway (Wise and Rompre, 1989). An established biochemical mechanism for nicotine-enhanced dopamine release is by activating presynaptic nicotinic acetylcholine receptors (nAChRs) (Wonnacott, 1997). Prolonged application of 10^-7 to 10^-5 M nicotine to striatal synaptosomes promoted a sustained efflux of [³H]dopamine. This nicotine effect was mediated by non-7 nAChRs, because it was blocked by 5 µM mecamylamine but was resistant to 100 nM -bungarotoxin (BgTx). Dopamine release was diminished by omitting Na⁺ or by applying peptide calcium channel blockers, indicating that nAChRs trigger release by depolarizing the nerve terminals. However, because 7 receptors rapidly desensitize in the continuous presence of agonists, a repetitive stimulation protocol was used to evaluate the possible significance of desensitization. This protocol produced a transient increase in [³H]dopamine released by depolarization and a significant increase in the response to hypertonic solutions that measure the size of the readily releasable pool (RRP) of synaptic vesicles. The nicotine-induced increase in the size of the readily releasable pool was blocked by BgTx and by the calmodulin antagonist calmidazolium, suggesting that Ca²⁺ entry through 7 nAChRs specifically enhances synaptic vesicle mobilization at dopamine terminals. Thus, nicotine enhances dopamine release by two complementary actions mediated by discrete nAChR subtypes and suggest that the 7 nAChR-mediated pathway is tightly and specifically coupled to refilling of the RRP of vesicles in dopamine terminals.

Key words: striatum; acetylcholine; presynaptic; kinetics; 7 nAChR; -bungarotoxin

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Received April 23, 2004; revised October 1, 2004; accepted November 5, 2004.

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