PT  - JOURNAL ARTICLE
AU  - B. Jill Venton
AU  - Andrew T. Seipel
AU  - Paul E. M. Phillips
AU  - William C. Wetsel
AU  - Daniel Gitler
AU  - Paul Greengard
AU  - George J. Augustine
AU  - R. Mark Wightman
TI  - Cocaine Increases Dopamine Release by Mobilization of a Synapsin-Dependent Reserve Pool
AID  - 10.1523/JNEUROSCI.4901-04.2006
DP  - 2006 Mar 22
TA  - The Journal of Neuroscience
PG  - 3206--3209
VI  - 26
IP  - 12
4099  - http://www.jneurosci.org/content/26/12/3206.short
4100  - http://www.jneurosci.org/content/26/12/3206.full
SO  - J. Neurosci.2006 Mar 22; 26
AB  - 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 α-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.