Document Detail

Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals.
MedLine Citation:
PMID:  23303926     Owner:  NLM     Status:  MEDLINE    
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-dose AMPH, 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.
D P Daberkow; H D Brown; K D Bunner; S A Kraniotis; M A Doellman; M E Ragozzino; P A Garris; M F Roitman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  33     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-10     Completed Date:  2013-03-04     Revised Date:  2013-07-18    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  452-63     Citation Subset:  IM    
School of Biological Sciences, Cell Biology, Physiology and Development Section, Illinois State University, Normal, Illinois 61790, USA.
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MeSH Terms
Amphetamines / pharmacology*
Conditioning, Operant / drug effects
Discrimination Learning / drug effects
Dopamine / metabolism*,  physiology*
Dopamine Plasma Membrane Transport Proteins / metabolism
Dopamine Uptake Inhibitors / pharmacology*
Dopaminergic Neurons / drug effects,  metabolism
Dose-Response Relationship, Drug
Electric Stimulation
Electrodes, Implanted
Exocytosis / drug effects*
Rats, Sprague-Dawley
Signal Transduction / drug effects
Synaptic Transmission / drug effects
Grant Support
Reg. No./Substance:
0/Amphetamines; 0/Dopamine Plasma Membrane Transport Proteins; 0/Dopamine Uptake Inhibitors
Comment In:
J Neurosci. 2013 May 22;33(21):8923-5   [PMID:  23699503 ]

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