Phasic Mesolimbic Dopamine Signaling Encodes the Facilitation of Incentive Motivation Produced by Repeated Cocaine Exposure

Abstract

Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.

Prior Cocaine Experience Impairs Normal Phasic Dopamine Signals of Reward Value in Accumbens Shell

“…Typically in associative learning, phasic DA immediately following cue presentation scales with anticipated reward value Jones et al, 2010;Ostlund et al, 2014;Saddoris et al, 2015b;Sugam et al, 2012;Wassum et al, 2013). However, DA release for unsignaled rewards in the present study followed a different pattern, as Early-Phase DA in the present study did not distinguish reward value in either the core or the shell.…”

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation

“…Activating mAChR autoreceptors on striatal cholinergic interneurons, which can decrease acetylcholine tone at nAChRs on dopamine terminals, can also augment terminal dopamine release to high-frequency stimulation (Shin et al, 2015;Threlfell et al, 2010). Not only is it well established that reward-predictive cues trigger burst firing in dopamine cells (Schultz, 2001), but there is growing evidence that the resulting dopamine release in the NAc mediates cue-motivated instrumental behavior (Lex and Hauber, 2008;Ostlund et al, 2014b;Peciña and Berridge, 2013). Combined, these data suggest that blockade of nAChR could enhance the dopamine response to reward-predictive cues, whereas antagonizing mAChRs could blunt it.…”

“…This has been previously demonstrated as a reliable measure of task-related and cue-evoked dopamine signaling (Aitken et al, 2016;Ostlund et al, 2014b;Wassum et al, 2013). Because previous data have demonstrated CS + -induced elevations in NAc dopamine signaling during PIT (Aitken et al, 2016;Ostlund et al, 2014b;Wassum et al, 2013), planned comparisons were used when comparing peak dopamine concentration during the CS + vs CS Ø . The average of the background-subtracted dopamine concentration change during the entire 2-min CS period served as a measure of more prolonged CS-induced dopamine concentration changes.…”

“…The behavioral effects of NAc nAChR and mAChR inactivation were complimented by data showing a corresponding influence of these treatments to enhance or attenuate, respectively, cue onset-evoked NAc dopamine signaling, which has been both correlated with (Aitken et al, 2016;Ostlund et al, 2014b;Wassum et al, 2013) and causally implicated in (Lex and Hauber, 2008;Peciña and Berridge, 2013;Wyvell and Berridge, 2000) the motivating influence of cues over reward-seeking activity. Of note, under control conditions, dopamine was found to be elevated at CS + onset and to return to baseline within~30 s, similar to our recent report (Aitken et al, 2016), but shorter-lasting than the cueevoked dopamine response detected during PIT in the earlier work (Wassum et al, 2013).…”

“…For Experiment 2, calibrated carbon-fiber microelectrodes coupled with guide cannulae were implanted unilaterally into the NAc (AP: +1.3 mm; ML: ± 1.3; V: − 7.0 from dura) along with an Ag/AgCl reference electrode in the contralateral cortex. Coordinates were selected to match our previous NAc core dopamine recording location during PIT (Aitken et al, 2016;Ostlund et al, 2014b;Wassum et al, 2013) and to avoid electrode place in the anterior commissure. Electrode/cannula probes were arranged such that the electrode tip was aligned to the coordinate above, with the cannula positioned more laterally parallel to the coronal suture.…”