title: Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals.
abstract: 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.
authors.affiliation: School of Biological Sciences, Cell Biology, Physiology and Development Section, Illinois State University, Normal, Illinois 61790, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Daberkow
authors.forename: H D
authors.initials: HD
authors.lastname: Brown
authors.forename: K D
authors.initials: KD
authors.lastname: Bunner
authors.forename: S A
authors.initials: SA
authors.lastname: Kraniotis
authors.forename: M A
authors.initials: MA
authors.lastname: Doellman
authors.forename: M E
authors.initials: ME
authors.lastname: Ragozzino
authors.forename: P A
authors.initials: PA
authors.lastname: Garris
authors.forename: M F
authors.initials: MF
authors.lastname: Roitman
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004563:Electrochemistry; D004567:Electrodes, Implanted; D005089:Exocytosis / Q000187:drug effects*; D008297:Male; D008839:Microelectrodes; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000662:Amphetamines; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D004298:Dopamine