Understanding the shift to compulsion in addiction: insights from personality traits, social factors, and neurobiology.

Compulsion stands as a central symptom of drug addiction; however, only a small fraction of individuals who use drugs exhibit compulsive characteristics. Differences observed in Sign-trackers (ST) and Goal-trackers (GT) during Pavlovian conditioning may shed light on individual variances in drug addiction. Here, we focus on the behavioral attributes, formation processes, and neural mechanisms underlying ST and how they drive addiction toward compulsivity in humans. We will explore addiction from three interconnected levels: individual personality traits, social factors, and neurobiology. Furthermore, we distinguish between the processes of sensitization and habituation within ST. These nuanced distinctions across various aspects of addiction will contribute to our understanding of the addiction development process and the formulation of targeted preventive strategies.

Inhibition of a cortico-thalamic circuit attenuates cue-induced reinstatement of drug-seeking behavior in "relapse prone" male rats.

RATIONALE: Relapse often occurs when individuals are exposed to stimuli or cues previously associated with the drug-taking experience. The ability of drug cues to trigger relapse is believed to be a consequence of incentive salience attribution, a process by which the incentive value of reward is transferred to the reward-paired cue. Sign-tracker (ST) rats that attribute enhanced incentive value to reward cues are more prone to relapse compared to goal-tracker (GT) rats that primarily attribute predictive value to such cues. OBJECTIVES: The neurobiological mechanisms underlying this individual variation in relapse propensity remains largely unexplored. The paraventricular nucleus of the thalamus (PVT) has been identified as a critical node in the regulation of cue-elicited behaviors in STs and GTs, including cue-induced reinstatement of drug-seeking behavior. Here we used a chemogenetic approach to assess whether "top-down" cortical input from the prelimbic cortex (PrL) to the PVT plays a role in mediating individual differences in relapse propensity. RESULTS: Chemogenetic inhibition of the PrL-PVT pathway selectively decreased cue-induced reinstatement of drug-seeking behavior in STs, without affecting behavior in GTs. In contrast, cocaine-primed drug-seeking behavior was not affected in either phenotype. Furthermore, when rats were characterized based on a different behavioral phenotype-locomotor response to novelty-inhibition of the PrL-PVT pathway had no effect on either cue- or drug-induced reinstatement. CONCLUSIONS: These results highlight an important role for the PrL-PVT pathway in vulnerability to relapse that is consequent to individual differences in the propensity to attribute incentive salience to discrete reward cues.

Transient inactivation of the paraventricular nucleus of the thalamus enhances cue-induced reinstatement in goal-trackers, but not sign-trackers.

RATIONALE: The paraventricular nucleus of the thalamus (PVT) has been shown to mediate cue-motivated behaviors, such as sign- and goal-tracking, as well as reinstatement of drug-seeking behavior. However, the role of the PVT in mediating individual variation in cue-induced drug-seeking behavior remains unknown. OBJECTIVES: This study aimed to determine if inactivation of the PVT differentially mediates cue-induced drug-seeking behavior in sign-trackers and goal-trackers. METHODS: Rats were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their Pavlovian conditioned approach behavior. Rats were then exposed to 15 days of cocaine self-administration, followed by a 2-week forced abstinence period and then extinction training. Rats then underwent tests for cue-induced reinstatement and general locomotor activity, prior to which they received an infusion of either saline (control) or baclofen/muscimol (B/M) to inactivate the PVT. RESULTS: Relative to control animals of the same phenotype, GTs show a robust increase in cue-induced drug-seeking behavior following PVT inactivation, whereas the behavior of STs was not affected. PVT inactivation did not affect locomotor activity in either phenotype. CONCLUSION: In GTs, the PVT appears to inhibit the expression of drug-seeking, presumably by attenuating the incentive value of the drug cue. Thus, inactivation of the PVT releases this inhibition in GTs, resulting in an increase in cue-induced drug-seeking behavior. PVT inactivation did not affect cue-induced drug-seeking behavior in STs, suggesting that the role of the PVT in encoding the incentive motivational value of drug cues differs between STs and GTs.

Sex and Adolescent Ethanol Exposure Influence Pavlovian Conditioned Approach.

BACKGROUND: Alcohol use among adolescents is widespread and a growing concern due to long-term behavioral deficits, including altered Pavlovian behavior, that potentially contribute to addiction vulnerability. We tested the hypothesis that adolescent intermittent ethanol (AIE) exposure alters Pavlovian behavior in males and females as measured by a shift from goal-tracking to sign-tracking. Additionally, we investigated GLT-1, an astrocytic glutamate transporter, as a potential contributor to a sign-tracking phenotype. METHODS: Male and female Sprague-Dawley rats were exposed to AIE (5 g/kg, intragastric) or water intermittently 2 days on and 2 days off from postnatal day (P) 25 to 54. Around P70, animals began 20 daily sessions of Pavlovian conditioned approach (PCA), where they learned that a cue predicted noncontingent reward delivery. Lever pressing indicated interaction with the cue, or sign-tracking, and receptacle entries indicated approach to the reward delivery location, or goal-tracking. To test for effects of AIE on nucleus accumbens (NAcc) excitatory signaling, we isolated membrane subfractions and measured protein levels of the glutamate transporter GLT-1 after animals completed behavior as a measure of glutamate homeostasis. RESULTS: Females exhibited elevated sign-tracking compared to males with significantly more lever presses, faster latency to first lever press, and greater probability to lever press in a trial. AIE significantly increased lever pressing while blunting goal-tracking, as indicated by fewer cue-evoked receptacle entries, slower latency to receptacle entry, and lower probability to enter the receptacle in a trial. No significant sex-by-exposure interactions were observed in sign- or goal-tracking metrics. Moreover, we found no significant effects of sex or exposure on membrane GLT-1 expression in the NAcc. CONCLUSIONS: Females exhibited enhanced sign-tracking compared to males, while AIE decreased goal-tracking compared to control exposure. Our findings support the hypothesis that adolescent binge ethanol can shift conditioned behavior from goal- to cue-directed in PCA, especially in females.

Individual differences in the influence of task-irrelevant Pavlovian cues on human behavior.

Pavlovian-to-instrumental transfer (PIT) refers to the process of a Pavlovian reward-paired cue acquiring incentive motivational proprieties that drive choices. It represents a crucial phenomenon for understanding cue-controlled behavior, and it has both adaptive and maladaptive implications (i.e., drug-taking). In animals, individual differences in the degree to which such cues bias performance have been identified in two types of individuals that exhibit distinct Conditioned Responses (CR) during Pavlovian conditioning: Sign-Trackers (ST) and Goal-Trackers (GT). Using an appetitive PIT procedure with a monetary reward, the present study investigated, for the first time, the extent to which such individual differences might affect the influence of reward-paired cues in humans. In a first task, participants learned an instrumental response leading to reward; then, in a second task, a visual Pavlovian cue was associated with the same reward; finally, in a third task, PIT was tested by measuring the preference for the reward-paired instrumental response when the task-irrelevant reward-paired cue was presented, in the absence of the reward itself. In ST individuals, but not in GT individuals, reward-related cues biased behavior, resulting in an increased likelihood to perform the instrumental response independently paired with the same reward when presented with the task-irrelevant reward-paired cue, even if the reward itself was no longer available (i.e., stronger PIT effect). This finding has important implications for developing individualized treatment for maladaptive behaviors, such as addiction.

Experimental predictions drawn from a computational model of sign-trackers and goal-trackers.

Gaining a better understanding of the biological mechanisms underlying the individual variation observed in response to rewards and reward cues could help to identify and treat individuals more prone to disorders of impulsive control, such as addiction. Variation in response to reward cues is captured in rats undergoing autoshaping experiments where the appearance of a lever precedes food delivery. Although no response is required for food to be delivered, some rats (goal-trackers) learn to approach and avidly engage the magazine until food delivery, whereas other rats (sign-trackers) come to approach and engage avidly the lever. The impulsive and often maladaptive characteristics of the latter response are reminiscent of addictive behaviour in humans. In a previous article, we developed a computational model accounting for a set of experimental data regarding sign-trackers and goal-trackers. Here we show new simulations of the model to draw experimental predictions that could help further validate or refute the model. In particular, we apply the model to new experimental protocols such as injecting flupentixol locally into the core of the nucleus accumbens rather than systemically, and lesioning of the core of the nucleus accumbens before or after conditioning. In addition, we discuss the possibility of removing the food magazine during the inter-trial interval. The predictions from this revised model will help us better understand the role of different brain regions in the behaviours expressed by sign-trackers and goal-trackers.

Individual variation in the propensity to attribute incentive salience to a food cue: influence of sex.

There is considerable individual variation in the propensity of animals to attribute incentive salience to discrete reward cues, but to date most of this research has been conducted in male rats. The purpose of this study was to determine whether sex influences the propensity to attribute incentive salience to a food cue, using rats from two different outbred strains (Sprague-Dawley [SD] and Heterogeneous Stock [HS]). The motivational value of a food cue was assessed in two ways: (i) by the ability of the cue to elicit approach toward it and (ii) by its ability to act as a conditioned reinforcer. We found that female SD rats acquired Pavlovian conditioned approach behavior slightly faster than males, but no sex difference was detected in HS rats, and neither strain showed a sex difference in asymptotic performance of approach behavior. Moreover, female approach behavior did not differ across estrous cycle. Compared to males, females made more active responses during the test for conditioned reinforcement, although they made more inactive responses as well. We conclude that although there are small sex differences in performance on these tasks, these are probably not due to a notable sex difference in the propensity to attribute incentive salience to a food cue.