title: Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling.
abstract: Methamphetamine (METH) is a highly addictive drug that is also neurotoxic to central dopamine (DA) systems. Although striatal DA depletions induced by METH are associated with behavioral and cognitive impairments, the link between these phenomena remains poorly understood. Previous work in both METH-pretreated animals and the 6-hydroxydopamine model of Parkinson's disease suggests that a disruption of phasic DA signaling, which is important for learning and goal-directed behavior, may be such a link. However, previous studies used electrical stimulation to elicit phasic-like DA responses and were also performed under anesthesia, which alters DA neuron activity and presynaptic function. Here we investigated the consequences of METH-induced DA terminal loss on both electrically evoked phasic-like DA signals and so-called 'spontaneous' phasic DA transients measured by voltammetry in awake rats. Not ostensibly attributable to discrete stimuli, these subsecond DA changes may play a role in enhancing reward-cue associations. METH pretreatment reduced tissue DA content in the dorsomedial striatum and nucleus accumbens by ~55%. Analysis of phasic-like DA responses elicited by reinforcing stimulation revealed that METH pretreatment decreased their amplitude and underlying mechanisms for release and uptake to a similar degree as DA content in both striatal subregions. Most importantly, characteristics of DA transients were altered by METH-induced DA terminal loss, with amplitude and frequency decreased and duration increased. These results demonstrate for the first time that denervation of DA neurons alters naturally occurring DA transients and are consistent with diminished phasic DA signaling as a plausible mechanism linking METH-induced striatal DA depletions and cognitive deficits.
authors.affiliation: Cell Biology, Physiology & Development Section, School of Biological Sciences, Illinois State University, 210 Julian Hall, Normal, IL, 61790-4120, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Howard
authors.forename: David P
authors.initials: DP
authors.lastname: Daberkow
authors.forename: Eric S
authors.initials: ES
authors.lastname: Ramsson
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Keefe
authors.forename: Paul A
authors.initials: PA
authors.lastname: Garris
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission
chemical_list: D015259:Dopamine Agents; D008694:Methamphetamine; D004298:Dopamine
keywords: psychostimulant; rat; striatum; transient; voltammetry