Attribution Of Incentive Salience Research Articles

Incentive-salience attribution is attenuated in spontaneously hypertensive rats, an animal model of ADHD

Spontaneously Hypertensive Rats (SHR) have been extensively studied as an animal model of Attention Deficit Hyperactivity Disorder (ADHD) because they show some of the defining features of that disorder, like some forms of impulsivity and hyperactivity. However, other characteristics of the disorder, like a deficit in motivation, have been scarcely studied in the SHR strain. In the present report, we studied in 45 SHR and 45 Wistar rats as a comparison group, the capacity of attribution of incentive salience to a stimulus predictor of reinforcement, which has become a central concept in the study of motivation. We employed the Pavlovian Conditioned-Approach (PCA) task, in which a lever is presented 8 s before a pellet is delivered. The attribution of incentive salience is indicated by responses to the lever, in contrast to the absence of attribution of incentive salience, which is indicated by entrances to the pellet receptacle. For quantifying the attribution of incentive salience, we employed the PCA index, which integrates three related variables for each type of response, lever presses and entrances to the feeder: 1) the number of responses, 2) the latency to the first response, and 3) the probability that at least one response occurred during the presence of the lever. SHR showed lower levels of PCA, suggesting a deficit in the attribution of incentive salience to the lever. This finding replicates the results reported by previous research that compared SHR’s performance in the PCA task against that of Sprague-Dawley rats.

Risk-promoting effects of reward-paired cues in human sign- and goal-trackers

Animal research suggests trait-like individual variation in the degree of incentive salience attribution to reward-predictive cues, defined phenotypically as sign-tracking (high) and goal-tracking (low incentive salience attribution). While these phenotypes have been linked to addiction features in rodents, their translational validity is less clear. Here, we examined whether sign- and goal-tracking in healthy human volunteers modulates the effects of reward-paired cues on decision making. Sign-tracking was measured in a Pavlovian conditioning paradigm as the amount of eye gaze fixation on the reward-predictive cue versus the location of impending reward delivery. In Study 1 (Cherkasova et al., 2018), participants were randomly assigned to perform a binary choice task in which rewards were either accompanied (cued, n = 63) or unaccompanied (uncued, n = 68) by money images and casino jingles. In Study 2, participants (n = 58) performed cued and uncued versions of the task in a within-subjects design. Across both studies, cues promoted riskier choice. Sign-tracking was not associated with risky choice in either study. Goal-tracking rather than sign-tracking was significantly associated with greater risk-promoting effects of cues in Study 1 but not in Study 2, although the direction of findings was consistent across both studies. These findings are at odds with the notion of sign-trackers being preferentially susceptible to the influence of reward cues on behavior and point to the role of mechanisms besides incentive salience in mediating such influences.

Inhibition of Dopamine Neurons Prevents Incentive Value Encoding of a Reward Cue: With Revelations from Deep Phenotyping.

The survival of an organism is dependent on its ability to respond to cues in the environment. Such cues can attain control over behavior as a function of the value ascribed to them. Some individuals have an inherent tendency to attribute reward-paired cues with incentive motivational value, or incentive salience. For these individuals, termed sign-trackers, a discrete cue that precedes reward delivery becomes attractive and desirable in its own right. Prior work suggests that the behavior of sign-trackers is dopamine-dependent, and cue-elicited dopamine in the NAc is believed to encode the incentive value of reward cues. Here we exploited the temporal resolution of optogenetics to determine whether selective inhibition of ventral tegmental area (VTA) dopamine neurons during cue presentation attenuates the propensity to sign-track. Using male tyrosine hydroxylase (TH)-Cre Long Evans rats, it was found that, under baseline conditions, ∼84% of TH-Cre rats tend to sign-track. Laser-induced inhibition of VTA dopamine neurons during cue presentation prevented the development of sign-tracking behavior, without affecting goal-tracking behavior. When laser inhibition was terminated, these same rats developed a sign-tracking response. Video analysis using DeepLabCutTM revealed that, relative to rats that received laser inhibition, rats in the control group spent more time near the location of the reward cue even when it was not present and were more likely to orient toward and approach the cue during its presentation. These findings demonstrate that cue-elicited dopamine release is critical for the attribution of incentive salience to reward cues.SIGNIFICANCE STATEMENT Activity of dopamine neurons in the ventral tegmental area (VTA) during cue presentation is necessary for the development of a sign-tracking, but not a goal-tracking, conditioned response in a Pavlovian task. We capitalized on the temporal precision of optogenetics to pair cue presentation with inhibition of VTA dopamine neurons. A detailed behavioral analysis with DeepLabCutTM revealed that cue-directed behaviors do not emerge without dopamine neuron activity in the VTA. Importantly, however, when optogenetic inhibition is lifted, cue-directed behaviors increase, and a sign-tracking response develops. These findings confirm the necessity of dopamine neuron activity in the VTA during cue presentation to encode the incentive value of reward cues.

Impaired cognitive control moderates the relation between the attribution of incentive salience and severity of consumption in patients with methamphetamine dependence

BackgroundCognitive control and the attribution of incentive salience are two key neuropsychological processes proposed to explain substance use disorder (SUD). However, little is known about how they interact to influence the severity of drug use in people with SUD. ObjectiveTo determine if cognitive control exerts a moderating effect on the relation between the attribution of salience to drug/reward-related cues and the severity of drug use in SUD cases. MethodSixty-nine SUD cases with methamphetamine as the main drug of consumption were selected and evaluated. Participants performed the Stroop, Go/No-Go, and Flanker tasks to identify a latent cognitive control factor, and the Effort-Expenditure for Reward task, as well as answering the Methamphetamine Incentive Salience Questionnaire to measure the attribution of incentive salience. Severity of drug use was determined by the KMSK scale and an exploratory clinical interview. ResultsAs expected, higher incentive salience attribution predicted greater severity of methamphetamine use. Unexpectedly, however, we found a moderating effect of impaired cognitive control on the relations between higher incentive salience scores and higher monthly drug use, and between younger age at onset of systematic drug use and higher incentive salience scores. ConclusionResults show the moderating role of cognitive control on the relation between incentive salience attribution and severity of drug use in SUD cases, and help explain the chronic, relapsing nature of addiction, knowledge necessary to develop more precise prevention and treatment strategies.

Nicotinic and muscarinic acetylcholine receptor antagonism dose-dependently decreases sign- but not goal-tracking behavior in male rats.

Acetylcholinergic antagonists have shown some promise in reducing addiction-related behaviors in both preclinical and clinical studies. However, the psychological mechanisms by which these drugs are able to affect addictive behavior remain unclear. A particular key process for the development of addiction is the attribution of incentive salience to reward-related cues, which can be specifically measured in animals using a Pavlovian conditioned approach procedure. When confronted with a lever that predicts food delivery, some rats engage with the lever directly (i.e., they sign track), indicating attribution of incentive-motivational properties to the lever itself. In contrast, others treat the lever as a predictive cue and approach the location of impending food delivery (i.e., they goal track), without treating the lever itself as a reward. We tested whether systemic antagonism of the either nicotinic or muscarinic acetylcholine receptors would selectively affect sign- or goal-tracking behavior, indicating a selective effect on incentive salience attribution. A total of 98 male Sprague Dawley rats were either given the muscarinic antagonist scopolamine (100, 50, or 10µg/kg i.p.) or the nicotinic antagonist mecamylamine (0.3, 1.0, or 3mg/kg i.p.) before being trained on a Pavlovian conditioned approach procedure. Scopolamine dose-dependently decreased sign tracking behavior and increased goal-tracking behavior. Mecamylamine reduced sign-tracking but did not affect goal-tracking behavior. Antagonism of either muscarinic or nicotinic acetylcholine receptors can reduce incentive sign-tracking behavior in male rats. This effect appears to be specifically due to a reduction in incentive salience attribution since goal-tracking either increased or was not affected by these manipulations.

Engineered highs: Reward variability and frequency as potential prerequisites of behavioural addiction

Influential learning-based accounts of substance addictions posit the attribution of incentive salience to drug-associated cues, and its escalation by the direct dopaminergic effects of drugs. In translating this account to disordered gambling, we have noted how the intermittent nature of monetary rewards in gambling (i.e. the variable ratio) may allow for analogous learning processes, via effects on dopaminergic signalling. The aim of the present article is to consider how multiple sources of reward variability operate within modern gambling products, and how similar sources of variability, as well as some novel sources of variability, also apply to other digital products implicated in behavioural addictions, including gaming, shopping, social media and online pornography. Online access to these activities facilitates not only unparalleled accessibility but also introduces novel forms of reward variability, as seen in the effects of infinite scrolls and personalized recommendations. We use the term uncertainty to refer to the subjective experience of reward variability. We further highlight two psychological factors that appear to moderate the effects of uncertainty: 1) the timecourse of uncertainty, especially with regard to its resolution, 2) the frequency of exposure, allowing temporal compression. Collectively, the evidence illustrates how qualitative and quantitative variability of reward can confer addictive potential to non-drug reinforcers by exploiting the psychological and neural processes that rely on predictability to guide reward seeking behaviour.

Reward-Mediated, Model-Free Reinforcement-Learning Mechanisms in Pavlovian and Instrumental Tasks Are Related.

Model-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based instrumental tasks parallel those engaged by pavlovian-based behavioral procedures. Recently, computational work has suggested that individual differences in the attribution of incentive salience to reward predictive cues, that is, sign- and goal-tracking behaviors, are also governed by variations in model-free and model-based value representations that guide behavior. Moreover, it is not appreciated if these systems that are characterized computationally using model-free and model-based algorithms are conserved across tasks for individual animals. In the current study, we used a within-subject design to assess sign-tracking and goal-tracking behaviors using a pavlovian conditioned approach task and then characterized behavior using an instrumental multistage decision-making (MSDM) task in male rats. We hypothesized that both pavlovian and instrumental learning processes may be driven by common reinforcement-learning mechanisms. Our data confirm that sign-tracking behavior was associated with greater reward-mediated, model-free reinforcement learning and that it was also linked to model-free reinforcement learning in the MSDM task. Computational analyses revealed that pavlovian model-free updating was correlated with model-free reinforcement learning in the MSDM task. These data provide key insights into the computational mechanisms mediating associative learning that could have important implications for normal and abnormal states.SIGNIFICANCE STATEMENT Model-free and model-based computations that guide instrumental decision-making processes may also be recruited in pavlovian-based behavioral procedures. Here, we used a within-subject design to test the hypothesis that both pavlovian and instrumental learning processes were driven by common reinforcement-learning mechanisms. Sign-tracking and goal-tracking behaviors were assessed in rats using a pavlovian conditioned approach task, and then instrumental behavior was characterized using an MSDM task. We report that sign-tracking behavior was associated with greater model-free, but not model-based, learning in the MSDM task. These data suggest that pavlovian and instrumental behaviors may be driven by conserved reinforcement-learning mechanisms.

Approximating the Manifold Structure of Attributed Incentive Salience from Large-scale Behavioural Data

Incentive salience attribution can be understood as a psychobiological mechanism ascribing relevance to potentially rewarding objects and actions. Despite being an important component of the motivational process guiding our everyday behaviour its study in naturalistic contexts is not straightforward. Here we propose a methodology based on artificial neural networks (ANNs) for approximating latent states produced by this process in situations where large volumes of behavioural data are available but no experimental control is possible. Leveraging knowledge derived from theoretical and computational accounts of incentive salience attribution we designed an ANN for estimating duration and intensity of future interactions between individuals and a series of video games in a large-scale (N > 3 × 106) longitudinal dataset. We found video games to be the ideal context for developing such methodology due to their reliance on reward mechanics and their ability to provide ecologically robust behavioural measures at scale. When compared to competing approaches our methodology produces representations that are better suited for predicting the intensity future behaviour and approximating some functional properties of attributed incentive salience. We discuss our findings with reference to the adopted theoretical and computational frameworks and suggest how our methodology could be an initial step for estimating attributed incentive salience in large-scale behavioural studies.

From skinner box to daily life: Sign-tracker phenotype co-segregates with impulsivity, compulsivity, and addiction tendencies in humans

Pavlovian conditioning holds the potential to incentivize environmental cues, leading to approach behavior toward them, even outside our awareness. Animal models suggest that this is particularly true for the so-called sign-tracker (ST) phenotype, which is considered to reflect a predisposition toward developing addiction-related behaviours. Despite its potential clinical relevance, few studies have demonstrated the translational validity of this model, likely due to difficulties in studying Pavlovian processes in humans. To fill this gap, we combined an ecological momentary assessment with ambulatory peripheral autonomic monitoring to test the hypothesis that traits associated with ST in preclinical studies would be associated with attribution of high incentive salience to reward-related cues. Several times for 2 days, participants were asked to rate the attractiveness of several preselected ecological rewards (e.g., coffee) and the preceding cues (the smell of coffee) while their electrocardiogram was recorded. While no absolute difference in subjective and physiological measures of motivational approach to daily cues compared with rewards emerged, individuals with high levels of impulsivity, obsessive-compulsive, and addiction-prone behaviors rated as more attractive and showed a greater increase in sympathetic arousal to cues versus rewards. The opposite pattern emerged for those with low levels in those dispositional traits, who responded more (both subjectively and physiologically) to rewards compared with their preceding cues. This study represents an attempt to answer the call to parcel complex behaviors into smaller constructs, improving the early detection of those who are vulnerable to develop psychopathological disorders, particularly in the domain of impulse control such as addiction.

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted for population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies.

Socioemotional deficit and HPA axis time response in high compulsive rats selected by schedule-induced polydipsia

Compulsivity is a failure to stop an ongoing behavior that has become inappropriate to the situation and is recognized as a transdiagnostic trait present in different neuropsychiatric disorders. The implication of motivation and emotion, as well as the stress response in compulsive population has not been fully understood. We assessed the motivation to reward and cues, the emotional response in different contexts and the hypothalamic-pituitary-adrenal (HPA) axis response in rats selected by a preclinical model of compulsive behavior. Firstly, high (HD) or low (LD) drinkers were selected according to their drinking behavior on schedule-induced polydipsia (SIP). Then, we assessed motivation by the propensity to attribute incentive salience to rewards on Pavlovian Conditioned Approach (PavCA) and motivation to gain reward on Progressive Ratio Schedule of Reinforcement (PRSR). Emotion was measured by Social Dominance on the Tube Test (SDTT) and emotional memory on Passive Avoidance (PA). Plasma corticosterone (CORT) levels in response to SIP were assessed. HD rats showed a socioemotional deficit by fewer victories on the SDTT, and an increased latency to enter the dark compartment on the PA. No differences were found between groups regarding to motivational assessment. Moreover, HD rats revealed a blunted time response in the increase of CORT levels at 45 min after SIP compared to LD rats. The findings show that the compulsive phenotype of HD rats exhibit less social dominance, more resistance to extinction and a differential CORT time response to SIP. These findings may contribute to highlight the relevance of assessing socioemotional behaviors and stress response for a better characterization of the vulnerability to compulsive spectrum disorders.

Behavioral response bias and event-related brain potentials implicate elevated incentive salience attribution to alcohol cues in emerging adults with lower sensitivity to alcohol.

This study used a behavioral approach-avoidance task including images of alcoholic beverages to test whether low sensitivity to alcohol (LS) is a phenotypical marker of a dispositional propensity to attribute bottom-up incentive value to naturally conditioned alcohol cues. Experimental study with a measured individual difference variable at a university psychology laboratory in Missouri, MO, USA. Participants were 178 emerging adults (aged 18-20 years) varying in self-reported sensitivity to alcohol's acute effects. Participants completed the alcohol approach-avoidance task while behavior (response time; RT) and the electroencephalogram (EEG) were recorded. Stimulus-locked event-related potentials (ERPs) provided indices of integrated (top-down and bottom-up) stimulus incentive value (P3 amplitude) and conflict between top-down task demands and bottom-up response propensities (N450 amplitude). Linear mixed models showed faster RT for 'alcohol-approach' relative to 'alcohol-avoid' trials for lower-sensitivity (LS) [meanD ± standard errorD (MD ± SED ) = 29.51 ± 9.74 ms, t(328) = 3.03, P = 0.003] but not higher-sensitivity (HS) individuals (MD ± SED = 2.27 ± 9.33 ms, t(328) = 0.243, P = 0.808). There was enhanced N450 amplitude (response conflict) for alcohol-avoid relative to alcohol-approach trials for LS participants (MD ± SED = 0.811 ± 0.198 μV, Z = 4.108, P < 0.001) and enhanced N450 amplitude for alcohol-approach relative to alcohol-avoid for HS participants (MD ± SED = 0.419 ± 0.188 μV, Z = 2.235, P = 0.025). There was also enhanced P3 amplitude for alcohol-approach relative to alcohol-avoid for LS (MD ± SED = 0.825 ± 0.204 μV, Z = 4.045, P < 0.001) but not HS (MD ± SED = 0.013 ± 0.194 μV, Z = 0.068, P = 0.946). Findings from a human laboratory study appear to support the notion that low sensitivity to alcohol indexes a propensity to attribute bottom-up incentive value to naturally conditioned alcohol cues.

Food addiction symptoms are related to neuroaffective responses to preferred binge food and erotic cues

It has been proposed that some individuals succumb to maladaptive eating behaviors because, like those with addiction, they attribute high incentive salience to food-associated cues. Here, we tested whether women that attribute high incentive salience to food-associated cues report high food addiction symptomatology. In 76 college women, we assessed self-reported food addiction symptoms using the Yale Food Addiction Scale and we recorded event-related potentials (ERPs, a direct measure of brain activity) to preferred food, erotic, unpleasant, and neutral images. We used the amplitude of the late positive potential (LPP, a component of the ERPs) as an index of the incentive salience attributed to the images. Using a multivariate classification algorithm (k-means cluster analysis), we identified two neuroaffective reactivity profiles that have been previously associated with individual differences in the tendency to attribute incentive salience to cues and with differences in vulnerability to addictive behaviors. Results showed that women with elevated LPP responses to preferred food cues relative to erotic images report higher food addiction symptoms than women with low LPP responses to preferred food cues relative to other motivationally relevant stimuli. These results support the hypothesis that individual differences in the tendency to attribute incentive salience to food cues play an important role in modulating food addiction symptomatology.

Relations Among Anhedonia, Reinforcement Learning, and Global Functioning in Help-seeking Youth.

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αβ = .22, 95% CI = 0.02, 0.48) and social functioning (αβ = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL.

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

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. 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 approachto assess whether "top-down" cortical input from the prelimbic cortex (PrL) to the PVT plays a role in mediating individual differences in relapse propensity. 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. 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.

Effects of dopamine receptor antagonism and amphetamine-induced psychomotor sensitization on sign- and goal-tracking after extended training

The dopamine system is important for incentive salience attribution, where motivational value is assigned to conditioned cues that predict appetitive reinforcers. However, the role of dopamine in this process may change with extended training. We tested the effects of dopamine D1-like and D2-like receptor antagonism on the expression of sign-tracking and goal-tracking conditioned responses following extended Pavlovian conditioned approach (PCA) training. We also tested if amphetamine-induced psychomotor sensitization accelerates the enhanced acquisition of sign-tracking that is observed with extended training. In experiment 1, 24 male Long-Evans rats received 20 PCA sessions in which one lever (CS+, 10 s) predicted 0.2 ml sucrose (10 %, w/v) delivery and the other lever (CS–) did not. SCH-23390 (D1-like antagonist) or eticlopride (D2-like antagonist) were administered before non-reinforced behavioural tests at doses of 0, 0.01, and 0.1 mg/kg (s.c.). In experiment 2, rats received vehicle or 2 mg/kg amphetamine (i.p.) for 7 days (n = 12/group). Ten days later, they received 16 PCA training sessions. Both doses of SCH-23390 reduced sign- and goal-tracking, but also reduced locomotor behaviour. A low dose of eticlopride (0.01 mg/kg) selectively reduced goal-tracking, without affecting sign-tracking or locomotor behaviour. Amphetamine produced psychomotor sensitization, and this did not affect the acquisition of sign- or goal-tracking. Following extended PCA training, dopamine D2-like receptor activity is required for the expression of goal-tracking but not sign-tracking. Psychomotor sensitization to amphetamine did not impact incentive salience attribution; however, more selective manipulations of the dopamine system may be needed.

Sensitivity to food and cocaine cues are independent traits in a large sample of heterogeneous stock rats

Sensitivity to cocaine and its associated stimuli (“cues”) are important factors in the development and maintenance of addiction. Rodent studies suggest that this sensitivity is related, in part, to the propensity to attribute incentive salience to food cues, which, in turn, contributes to the maintenance of cocaine self-administration, and cue-induced relapse of drug-seeking. Whereas each of these traits has established links to drug use, the relatedness between the individual traits themselves has not been well characterized in preclinical models. To this end, the propensity to attribute incentive salience to a food cue was first assessed in two distinct cohorts of 2716 outbred heterogeneous stock rats (HS; formerly N:NIH). We then determined whether each cohort was associated with performance in one of two paradigms (cocaine conditioned cue preference and cocaine contextual conditioning). These measure the unconditioned locomotor effects of cocaine, as well as conditioned approach and the locomotor response to a cocaine-paired floor or context. There was large individual variability and sex differences among all traits, but they were largely independent of one another in both males and females. These findings suggest that these traits may contribute to drug-use via independent underlying neuropsychological processes.

Sign tracking predicts cue-induced but not drug-primed reinstatement to methamphetamine seeking in rats: Effects of oxytocin treatment.

The incentive sensitisation theory of addiction posits that drug-associated stimuli become imbued with incentive motivational properties, driving pathological drug seeking. However, pre-existing variability in the incentive salience to non-drug reward cues ('sign trackers' (STs); 'goal trackers' (GTs)) is also predictive of the desire for and relapse to cocaine and opioids. Here, we asked whether variation in propensity to attribute incentive salience to a food cue is predictive of reinstatement to the highly addictive psychostimulant methamphetamine (METH), and whether treatment with the promising anti-addiction therapy oxytocin differentially reduces METH behaviour between STs and GTs. Rats were trained to associate a Pavlovian cue with delivery of a sucrose pellet over 8 days. They then received jugular vein catheters for intravenous METH self-administration, followed by behavioural extinction, and cue-induced and METH-primed reinstatement to METH-seeking behaviours. Oxytocin was administered prior to self-administration and reinstatement tests. Despite the self-administration of similar amounts of METH, STs reinstated more to METH cues than did GTs, yet METH-priming reinstated STs and GTs similarly. Furthermore, oxytocin attenuated cue-induced reinstatement more so in STs than in GTs, and reduced METH-primed reinstatement to a greater extent in the top quartile of reinstaters, indicating that oxytocin treatment may be most effective for those at highest risk of addiction. This pre-existing bias towards reward cues presents a possible tool to screen for METH addiction susceptibility and may be useful for understanding the neurobiology of addiction and for pharmacotherapeutic discovery.

Neurons of the Ventral Tegmental Area Encode Individual Differences in Motivational "Wanting" for Reward Cues.

It has been argued that the dopaminergic system is involved in the attribution of motivational value to reward predictive cues as well as prediction error. To evaluate, dopamine neurons were recorded from male rats performing a Pavlovian approach task containing cues that have both "predictive" and "incentive" properties. All animals learned the predictive nature of the cue (illuminated lever entry into cage), but some also found the cue to be attractive and were motivated toward it ("sign-trackers," STs). "Goal-trackers" (GTs) predominantly approached the location of reward receptacle. Rats were implanted with tetrodes for neural electrophysiological recordings in the ventral tegmental area. Cells were characterized by spike waveform shape and firing rate. Firing rates and magnitudes of responses in relation to Pavlovian behaviors, cue presentation, and reward delivery were assessed. We identified 103 dopamine and 141 nondopamine neurons. GTs and STs both showed responses to the initial lever presentation (CS1) and lever retraction (CS2). However, higher firing rates were sustained during the lever interaction period only in STs. Further, dopamine cells of STs showed a significantly higher proportion of cells responding to both CS1 and CS2. These are the first results to show that neurons from the VTA encode both predictive and incentive cues, support an important role for dopamine neurons in the attribution of incentive salience to reward-paired cues, and underscore the consequences of potential differences in motivational behavior between individuals.SIGNIFICANCE STATEMENT This project serves to determine whether dopamine neurons encode differences in cued approach behaviors and incentive salience. How neurons of the VTA affect signaling through the NAcc and subsequent dopamine release is still not well known. All cues that precede a reward are predictive in nature. Some, however, also have incentive value, in that they elicit approach toward them. We quantified the attribution of incentive salience through cue approach behavior and cue interaction, and the corresponding magnitude of VTA neural firing. We found dopamine neurons of the VTA encode strength of incentive salience of reward cues. This suggests that dopamine neurons specifically in the VTA encode motivation.

The lateral hypothalamus and orexinergic transmission in the paraventricular thalamus promote the attribution of incentive salience to reward-associated cues.

Prior research suggests that the neural pathway from the lateral hypothalamic area (LHA) to the paraventricular nucleus of the thalamus (PVT) mediates the attribution of incentive salience to Pavlovian reward cues. However, a causal role for the LHA and the neurotransmitters involved have not been demonstrated in this regard. To examine (1) the role of LHA in the acquisition of Pavlovian conditioned approach (PavCA) behaviors, and (2) the role of PVT orexin 1 receptors (OX1r) and orexin 2 receptors (OX2r) in the expression of PavCA behaviors and conditioned reinforcement. Rats received excitotoxic lesions of the LHA prior to Pavlovian training. A separate cohort of rats characterized as sign-trackers (STs) or goal-trackers (GTs) received the OX1r antagonist SB-334867, or the OX2r antagonist TCS-OX2-29, into the PVT, to assess their effects on the expression of PavCA behavior and on the conditioned reinforcing properties of a Pavlovian reward cue. LHA lesions attenuated the development of sign-tracking behavior. Administration of either the OX1r or OX2r antagonist into the PVT reduced sign-tracking behavior in STs. Further, OX2r antagonism reduced the conditioned reinforcing properties of a Pavlovian reward cue in STs. The LHA is necessary for the development of sign-tracking behavior; and blockade of orexin signaling in the PVT attenuates the expression of sign-tracking behavior and the conditioned reinforcing properties of a Pavlovian reward cue. Together, these data suggest that LHA orexin inputs to the PVT are a key component of the circuitry that encodes the incentive motivational value of reward cues.