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, prior 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 sub-second 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.

Changes in Neural Circuitry Regulating Response-Reversal Learning and Arc-Mediated Consolidation of Learning in Rats with Methamphetamine-Induced Partial Monoamine Loss

“…As confirmed in the present work, exposure to high doses of METH results in partial DA loss (Wagner et al, 1980). This loss is associated with impairment of phasic DA signaling (Howard et al, 2011(Howard et al, , 2013a, along with loss of transcriptional activation and normal subcellular distribution of Arc mRNA in dorsal striatum (Barker-Haliski et al, 2012a), both of which are critical for synaptic plasticity underlying basal ganglia-mediated learning and memory processes (Calabresi et al, 2007;Schultz, 2007). As previously reported (eg, Haughey et al, 1999;Johnson-Davis et al, 2002;Ricaurte et al, 1980;Wallace et al, 1999), in this study, METHinduced DA loss in the NAc, particularly in the shell, was less extensive.…”

“…Perhaps the B25% depletion in NAc shell observed in this study was insufficient to prevent this brain region from being used by METH-pretreated rats in the behavioral task. Although we have observed disruption of DA transients in the NAc core of METH-pretreated rats (Howard et al, 2013a), whether there is less significant disruption of phasic DA signaling in NAc shell at these levels of METH-induced DA loss remains to be determined.…”

“…As in human METH abusers (Dean et al, 2013), this partial monoamine loss is associated with cognitive deficits, including impairments in odor and object recognition, attentional setshifting (Marshall and O'Dell, 2012), sequential motor learning (Chapman et al, 2001;Daberkow et al, 2005), formation of stimulus-response associations (Son et al, 2011) and inhibitory control over behavior (Son et al, 2013). The deficits in basal ganglia-mediated behaviors may arise secondary to impaired phasic DA neurotransmission in the partially denervated striatum (Howard et al, 2011(Howard et al, , 2013a.…”

A Neurochemical Pattern Generator SoC With Switched-Electrode Management for Single-Chip Electrical Stimulation and 9.3 µW, 78 pA rms , 400 V/s FSCV Sensing

“…Precise neurochemical pattern generation could also have additional clinical bearing by providing the framework for ultimately developing new neuromodulation devices that can impose therapeutic neurochemical profiles or maintain optimal neurochemical levels in disease states via real-time feedback control [11]. One exciting application is directed at remediating cognitive deficits associated with the loss of brain dopamine neurons in Parkinson's disease (PD) and drug abuse, which appear to be related to dysfunction of phasic dopamine signaling [12]- [14]. Neurochemical pattern generation could be employed to activate these dynamic extracellular dopamine transients, which are reduced by neurodegeneration, with exacting temporal precision to restore the diminished dopamine control of postsynaptic cells and enhance cognitive function [15].…”

A Pipette-Based Calibration System for Fast-Scan Cyclic Voltammetry with Fast Response Times

“…This can be seen in other calibration schemes (1,7,17,33,34) and is the result of the adsorption of DA at slower (10 Hz) application frequencies (7) and a negative holding potential (1). Most endogenous or drug-related transient DA events in vivo are <1 s (35), so the sudden rise to peak (0.3 s) seen in the Simple system should be a good in vitro representation of a CFM's response to sudden changes of DA in vivo. While all experiments were conducted at room temperature (23C), the Simple system calibration method would theoretically be more sensitive to convective currents than would FIA.…”