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Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

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journal contribution
posted on 06.12.2013, 00:00 by D.P. Daberkow, H.D. Brown, K.D. Bunner, S.A. Kraniotis, M.A. Doellman, M.E. Ragozzino, P.A. Garris, M.F. Roitman
Drugs of abuse hijack brain-reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting nonexocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties, which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to 2 h. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration, and frequency of spontaneous dopamine transients, the naturally occurring, nonelectrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sugar reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sugar-predictive cues. However, operant behavior failed at high-doseAMPH,which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify upregulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling.

Funding

This work was supported by the National Institute on Drug Abuse (Grants DA021770 and DA024036 to P.A.G. and DA025634 to M.F.R.), the National Institute of Child Health and Human Development (Grant HD055751 to M.E.R.), the National Science Foundation (Grant DBI0754615 to P.A.G.) and Illinois State University (grants to P.A.G.).

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Publisher Statement

This is a copy of an article published in the Journal of Neuroscience © 2013 Society for Neuroscience. The publication is available at http://www.jneurosci.org/.

Citation

Daberkow DP, Brown HD, Bunner KD, Kraniotis SA, Doellman MA, Ragozzino ME, Garris PA, Roitman MF. Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals. Journal of Neuroscience. 2013 Jan 9;33(2):452-63. doi: 10.1523/JNEUROSCI.2136-12.2013.

Publisher

Society for Neuroscience

Language

en_US

issn

1529-2401

Issue date

01/01/2013

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