title: Biphasic mechanisms of amphetamine action at the dopamine terminal.
abstract: In light of recent studies suggesting that amphetamine (AMPH) increases electrically evoked dopamine release ([DA]o), we examined discrepancies between these findings and literature that has demonstrated AMPH-induced decreases in [DA]o. The current study has expanded the inventory of AMPH actions by defining two separate mechanisms of AMPH effects on [DA]o at high and low doses, one dopamine transporter (DAT) independent and one DAT dependent, respectively. AMPH concentrations were measured via microdialysis in rat nucleus accumbens after intraperitoneal injections of 1 and 10 mg/kg and yielded values of ∼10 and 200 nM, respectively. Subsequently, voltammetry in brain slices was used to examine the effects of low (10 nM), moderate (100 nM), and high (10 μM) concentrations of AMPH across a range of frequency stimulations (one pulse; five pulses, 20 Hz; 24 pulses, 60 Hz). We discovered biphasic, concentration-dependent effects in WT mice, in which AMPH increased [DA]o at low concentrations and decreased [DA]o at high concentrations across all stimulation types. However, in slices from DAT-KO mice, [DA]o was decreased by all concentrations of AMPH, demonstrating that AMPH-induced increases in [DA]o are DAT dependent, whereas the decreases at high concentrations are DAT independent. We propose that low AMPH concentrations are insufficient to disrupt vesicular sequestration, and therefore AMPH acts solely as a DAT inhibitor to increase [DA]o. When AMPH concentrations are high, the added mechanism of vesicular depletion leads to reduced [DA]o. The biphasic mechanisms observed here confirm and extend the traditional actions of AMPH, but do not support mechanisms involving increased exocytotic release.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Cody A
authors.initials: CA
authors.lastname: Siciliano
authors.forename: Erin S
authors.initials: ES
authors.lastname: Calipari
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferris
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
mesh_terms: D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D018490:Serotonin Agents / Q000494:pharmacology; D013997:Time Factors
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D018490:Serotonin Agents; D005277:Fenfluramine; D000661:Amphetamine; D004298:Dopamine
keywords: dopamine transporter; knock-out; nucleus accumbens; phasic; tonic; voltammetry
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