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The Journal of Neuroscience, March 22, 2006, 26(12):3206-3209; doi:10.1523/JNEUROSCI.4901-04.2006

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Brief Communications
Cocaine Increases Dopamine Release by Mobilization of a Synapsin-Dependent Reserve Pool

B. Jill Venton,¹ Andrew T. Seipel,¹ Paul E. M. Phillips,² William C. Wetsel,³ Daniel Gitler,⁴ Paul Greengard,⁵ George J. Augustine,⁴ and R. Mark Wightman¹

¹Department of Chemistry and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, ²Department of Psychiatry and Behavioral Sciences and Department of Pharmacology, University of Washington, Seattle, Washington 98195, ³Departments of Psychiatry and Behavioral Sciences, Medicine (Endocrinology), and Cell Biology, and Mouse Behavioral and Neuroendocrine Analysis Core Facility, and ⁴Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, and ⁵Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York 10021

Correspondence should be addressed to R. Mark Wightman, Department of Chemistry, University of North Carolina, Venable Hall Campus Box 3290, Chapel Hill, NC 27599-3290. Email: rmw{at}unc.edu

Cocaine primarily exerts its behavioral effects by enhancing dopaminergic neurotransmission, amplifying dopamine-encoded sensorimotor integration. The presumed mechanism for this effect is inhibition of the dopamine transporter, which blocks dopamine uptake and prolongs the duration of dopamine in the extracellular space. However, there is growing evidence that cocaine can also augment dopamine release. Here, we directly monitored the actions of cocaine on dopamine release by using electrochemical detection to measure extracellular dopamine in the striatum of anesthetized mice. Cocaine enhanced the levels of striatal dopamine produced by electrical stimulation of dopaminergic neurons. Even after pretreatment with -methyl-p-tyrosine, which depletes the readily releasable pool of dopamine, cocaine was still capable of elevating dopamine levels. This suggests that cocaine enhances dopamine release by mobilizing a reserve pool of dopamine-containing synaptic vesicles. To test this hypothesis, we examined electrically evoked dopamine release in synapsin I/II/III triple knock-out mice, which have impaired synaptic vesicle reserve pools. Knock-out of synapsins greatly reduced the ability of cocaine to enhance dopamine release with long stimulus trains or after depletion of the newly synthesized pool. We therefore conclude that cocaine enhances dopamine release and does so by mobilizing a synapsin-dependent reserve pool of dopamine-containing synaptic vesicles. This capacity to enhance exocytotic release of dopamine may be important for the psychostimulant actions of cocaine.

Key words: cocaine; synapsin; dopamine; in vivo voltammetry; storage pools; psychostimulant

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Received Dec. 1, 2004; revised Feb. 3, 2006; accepted Feb. 4, 2006.

Correspondence should be addressed to R. Mark Wightman, Department of Chemistry, University of North Carolina, Venable Hall Campus Box 3290, Chapel Hill, NC 27599-3290. Email: rmw{at}unc.edu

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