Adolescent Alcohol Exposure Amplifies the Incentive Value of Reward-Predictive Cues Through Potentiation of Phasic Dopamine Signaling

Abstract

Adolescent alcohol use remains a major public health concern due in part to well-established findings implicating the age of onset in alcohol use in the development of alcohol use disorders and persistent decision-making deficits in adults. We have previously demonstrated that moderate adolescent alcohol consumption in rats promotes suboptimal decision making and an associated perturbation in mesolimbic dopamine transmission in adulthood. Dopamine-dependent incentive learning processes are an integral component of value-based decision making and a fundamental element to many theoretical accounts of addiction. Thus we tested the hypothesis that adolescent alcohol use selectively alters incentive learning processes through perturbation of mesolimbic dopamine systems. To assess incentive learning, behavioral and neurochemical measurements were made during the acquisition, maintenance, extinction, and reacquisition of a Pavlovian conditioned approach procedure in adult rats with a history of adolescent alcohol consumption. We show that moderate adolescent alcohol consumption potentiates stimulus-evoked phasic dopamine transmission, measured in vivo by fast-scan cyclic voltammetry, in adulthood and biases individuals toward a dopamine-dependent incentive learning strategy. Moreover, we demonstrate that animals exposed to alcohol in adolescence are more sensitive to an unexpected variation in reward outcomes. This pattern of phasic dopamine signaling and the associated bias in learning may provide a mechanism for the well-documented vulnerability of individuals with early-life alcohol use for alcohol use disorders in adulthood.

Figure 1

(a) Procedural timeline of the experiments. (b) Adolescent alcohol consumption during PND 30–49 was stable across the 20-day continuous exposure period. (c) Animals exposed to either control or alcohol gelatin increased in body weight to a similar extent. (d) Coronal sections of the rat brain showing the recording sites in the nucleus accumbens core (Adapted from Paxinos and Watson, 2004).

Figure 2

Behavioral responses during the Pavlovian conditioned approach task. (a) Analysis of response bias (lever presses−food cup entries)/(lever presses+food cup entries), a measure of the relative allocation of behavioral responses, revealed that animals exposed to alcohol during adolescence mainly show CRs to the reward-predictive cue. (b) A frequency distribution of response bias scores during the last session of training indicates that animals exposed to alcohol during adolescence shifted the distribution of responses exclusively towards a sign-tracking CR. (c) Over the course of learning, alcohol-exposed animals reduced their CR towards the food cup, whereas control-treated animals continued to approach the food cup. (d) CRs to the reward-predicting lever increased in both groups over training. Data are represented as means+SEM. *Indicates significant difference between groups with post-hoc t-tests with a Bonferroni correction (p<0.05).

Figure 3

Phasic dopamine signaling during the first and final sessions of Pavlovian conditioned approach behavior. (a, b) Representative traces from the first session and corresponding background-subtracted cyclic voltammograms (inset) depict changes in dopamine oxidative current within the nucleus accumbens core in response to CS presentation (grey arrowhead) after 5 s and US delivery (black arrowhead) after 13 s in control (a) and alcohol-exposed animals (b). The pseudocolor plots depict color-coded observed changes in redox currents as a function of applied potential (y axis) plotted over time (x axis). (c) Average trace of dopamine transmission in a 20-s window around CS and US presentation over the first 25 trials of Pavlovian conditioning. (c: inset) Peak dopamine values for CS and US responses for alcohol- and control-treated animals in the first Pavlovian session. (d) Average trace of dopamine transmission in a 20-s window around CS and US presentation over the final 25 trials of Pavlovian conditioning. Data are represented as means+SEM. *Difference between groups (one-way ANOVA, p<0.05).

Figure 4

CS- and US-evoked phasic dopamine signaling across training in animals classified as sign trackers. (a) A frequency distribution of response bias scores during the last session of training. The gray bar indicates animals with a response bias score >0.70 that were included in voltammetric analyses in panels (b) and (c). (b) CS-evoked dopamine in the alcohol and control groups throughout training. (c) US-evoked dopamine in the alcohol and control groups throughout training. *Indicates significant difference between groups with post-hoc t-tests with a Bonferroni correction (p<0.05).

Figure 5

Behavioral responses and CS-evoked phasic dopamine signaling during extinction training. (a) The response bias score decreased equally in both groups. (b) The food cup-directed CR declined in control animals, whereas it remained unchanged for alcohol-exposed animals. (c) Conditioned responses towards the reward-predictive lever decreased across trials in both the groups. (d) CS-evoked phasic dopamine decreased across extinction equally in both groups. *Indicates significant difference between groups with post-hoc t-tests with a Bonferroni correction (p<0.05).

Figure 6

Behavioral (a–c) and dopaminergic responses (d, e) during reacquisition of Pavlovian conditioned approach behavior. (a) Alcohol-exposed animals showed a greater bias toward a sign-tracking response. (b) The CR toward the food cup mainly increased in control animals, whereas (c) both groups increased their CR for the reward-predicting lever. (d, e) CS- and US-evoked phasic dopamine signaling increased during reacquisition in both groups. (d) Adolescent alcohol consumption resulted in higher CS-evoked phasic dopamine release in the final trial bin of reacquisition in comparison to controls, as well as a (e) larger US-evoked phasic dopamine release in the first trial bin. Subsequently, in trial bins 2–5, both groups showed a decrease in US-evoked dopamine release, but signaling remained higher in alcohol-exposed animals. *Indicates significant difference between groups with post-hoc t-tests with a Bonferroni correction (p<0.05).

Figure 7

Phasic dopamine signaling in response to worse-than-expected, expected, and better-than-expected reward outcomes in control- and alcohol-treated animals. (a, b) Average dopamine traces for worse- (reward sizes 0 and 1) and better-than-expected (reward sizes 3 and 4) outcomes during the probe sessions where reward size was varied unpredictably. (c) CS-evoked dopamine release was not affected by altered reward sizes. (d) US-evoked dopamine release was sensitive to varying reward size in both groups but alcohol-treated animals showed greater overall responsiveness to unexpected variation in reward outcomes. *Indicates significant difference in US dopamine release between reward sizes in post hoc within group comparisons with a Bonferroni correction (p<0.05).