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.

Figure 1

Effect of cocaine preexposure on phasic mesolimbic DA signaling during PIT testing (see left panel for experimental design). (a) Mean change in lever pressing (CS−pre-CS; +SEM) during cue presentations for rats in groups saline and cocaine, plotted separately for CS+ (filled) and CS− (open) trials. (b) Mean change in DA concentration over 30-s CS periods, relative to last second of pre-CS period (background). See Figure 2 for representative and average DA by time traces. (c–e) Results of DA transient analysis. Mean (+SEM) DA transient amplitude (c), area (d), and frequency (e). Floating vertical lines show standard error of the mean difference (SED) for the simple effect of cue for each group and asterisks indicate significance at *p<0.05, **p<0.01, or ***p<0.001 for planned contrasts (two tailed). Results of linear mixed-model analyses are summarized in Table 1.

Figure 2

Representative PIT trial data from saline- and cocaine-treated rats. (a) Pseudocolor plots show voltammetric data as background-subtracted current (z axis in color) across applied scan potential (Eapp; y axis) over time (x axis), for CS+ (left) and CS− (right) trials. CS onset indicated by vertical dotted line. Peak DA oxidation occurs at approximately +0.6 V. Example current (y axis) by voltage (x axis) traces are placed to the right of each plot. Below the plots are traces showing fluctuations in estimated DA concentration (nM) over time. Peak times for identified DA transients are indicated by black circles and lever press times are indicated by Xs. (b) Mean change in DA concentration (+SEM, dotted lines) over consecutive 1 s periods during CS presentations, relative to 1 s pre-CS period, averaged across trials and subjects.

Figure 3

Normalized frequency of DA transients (+SEM) over time for 10-s epochs surrounding individual lever press actions (indicated by dotted vertical line) during CS+ (filled) and CS− (open) trials for saline- and cocaine-treated rats. The likelihood of DA transients increased during the initiation of lever pressing and decreased in the postpress period (quadratic effect of time bin: F_{9, 153}=44.12, p<0.001). A significant cue type × quadratic effect of time bin was also detected (F_{9, 153}=4.50, p<0.001), indicating that the temporal correlation was more pronounced during CS+ trials, although significant quadratic time bin effects were observed for trials with the CS+ (F_{9, 153}=28.97, p<0.001) and the CS− (F_{9, 153}=15.27, p<0.001). No other effect or interaction was significant. See Supplementary Figure S6 for further peri-response frequency distribution analysis.

Figure 4

Individual differences in CS+-evoked lever pressing and DA signaling. Scatterplots show relationship between change in lever press performance during CS+ trials (CS+−pre-CS+ y axis) and each of four measures of DA signaling (x axis): the amplitude (a), area (b), and frequency (c) of DA transients during CS+ trials, and the average change in DA concentration (d) during those trials. Data points (jittered) are for all trials with the CS+ for rats preexposed to saline or cocaine. Lines show regression slopes generated by linear mixed-model analysis, separately plotted for each group and for all rats. See Table 2 for regression coefficients and significance values for individual analyses. (e) Summary of the mediation (path) analysis. The mediated effect of cocaine exposure on reward seeking through DA signaling is the product of two distinct paths: path a is the total effect of cocaine exposure on DA signaling and path b is the direct effect of DA signaling on reward seeking that controls for the effect of cocaine. A bootstrapped estimate of the product of paths a and b, which represents the mediated effect, was significant. Unstandardized coefficients are shown for each path (*p<0.05).