Sign Trackers Research Articles

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.

Cortico-striatal action control inherent of opponent cognitive-motivational styles.

Turning on cue or stopping at a red light requires the detection of such cues to select action sequences, or suppress action, in accordance with cue-associated action rules. Cortico-striatal projections are an essential part of the brain's attention-motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic-DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns and initiated such turns more slowly than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In conjunction with turn cue-evoked glutamate spike levels, the presence of a single spike rendered GTs to be almost twice as likely to turn than STs. In contrast, multiple glutamate spikes predicted GTs to be less likely to turn than STs. In GTs, but not STs, inhibition of prelimbic-DMS projections attenuated turn rates, turn cue-evoked glutamate peaks, and increased the number of spikes. These findings suggest that turn cue-evoked glutamate release in GTs is tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals may be regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking.

Sign-tracking and goal-tracking in humans: Utilising eye-tracking in clinical and non-clinical populations

BackgroundIn Pavlovian conditioning, learned behaviour varies according to the perceived value of environmental cues. For goal-trackers (GT), the cue merely predicts a reward, whilst for sign-trackers (ST), the cue holds incentive value. The sign-tracking/goal-tracking model is well-validated in animals, but translational work is lacking. Despite the model’s relevance to several conditions, including attention deficit hyperactivity disorder (ADHD), we are unaware of any studies that have examined the model in clinical populations. MethodsThe current study used an eye-tracking Pavlovian conditioning paradigm to identify ST and GT in non-clinical (N = 54) and ADHD (N = 57) participants. Eye movements were recorded whilst performing the task. Dwell time was measured for two areas of interest: sign (i.e., cue) and goal (i.e., reward), and an eye-gaze index (EGI) was computed based on the dwell time sign-to-goal ratio. Higher EGI values indicate sign-tracking behaviour. ST and GT were determined using median and tertiary split approaches in both samples. ResultsDespite greater propensity for sign-tracking in those with ADHD, there was no significant difference between groups. The oculomotor conditioned response was reward-specific (CS+) and present, at least partly, from the start of the task indicating dispositional and learned components. There were no differences in externalising behaviours between ST and GT for either sample. ConclusionsSign-tracking is associated with CS+ trials only. There may be both dispositional and learned components to sign-tracking, potentially more common in those with ADHD. This holds translational potential for understanding individual differences in reward-learning.

Excitatory and Inhibitory Signaling in the Nucleus Accumbens Encode Different Aspects of a Pavlovian Cue in Sign Tracking and Goal Tracking Rats.

When a Pavlovian cue is presented separately from its associated reward, some animals will acquire a sign tracking (ST) response - approach and/or interaction with the cue - while others will acquire a goal tracking response - approach to the site of reward. We have previously shown that cue-evoked excitations in the nucleus accumbens (NAc) encode the vigor of both behaviors; in contrast, reward-related responses diverge over the course of training, possibly reflecting neurochemical differences between sign tracker and goal tracker individuals. However, a substantial subset of neurons in the NAc exhibit inhibitory, rather than excitatory, cue-evoked responses, and the evolution of their signaling during Pavlovian conditioning remains unknown. Using single-neuron recordings in behaving rats, we show that NAc neurons with cue-evoked inhibitions have distinct coding properties from neurons with cue-evoked excitations. Cue-evoked inhibitions become more numerous over the course of training and, like excitations, may encode the vigor of sign tracking and goal tracking behavior. However, the responses of cue-inhibited neurons do not evolve differently between sign tracker and goal tracker individuals. Moreover, cue-evoked inhibitions, unlike excitations, are insensitive to extinction of the cue-reward relationship. Finally, we show that cue-evoked excitations are greatly diminished by reward devaluation, while inhibitory cue responses are virtually unaffected. Overall, these findings converge with existing evidence that cue-excited neurons in NAc, but not cue-inhibited neurons, are profoundly sensitive to the same behavior variations that are often associated with changes in dopamine release.

Basal Forebrain Chemogenetic Inhibition Converts the Attentional Control Mode of Goal-Trackers to That of Sign-Trackers.

Sign tracking versus goal tracking in rats indicate vulnerability and resistance, respectively, to Pavlovian cue-evoked addictive drug taking and relapse. Here, we tested hypotheses predicting that the opponent cognitive-behavioral styles indexed by sign tracking versus goal tracking include variations in attentional performance which differentially depend on basal forebrain projection systems. Pavlovian Conditioned Approach (PCA) testing was used to identify male and female sign-trackers (STs) and goal-trackers (GTs), as well as rats with an intermediate phenotype (INTs). Upon reaching asymptotic performance in an operant task requiring the detection of visual signals (hits) as well as the reporting of signal absence for 40 min per session, GTs scored more hits than STs, and hit rates across all phenotypes correlated with PCA scores. STs missed relatively more signals than GTs specifically during the last 15 min of a session. Chemogenetic inhibition of the basal forebrain decreased hit rates in GTs but was without effect in STs. Moreover, the decrease in hits in GTs manifested solely during the last 15 min of a session. Transfection efficacy in the horizontal limb of the diagonal band (HDB), but not substantia innominate (SI) or nucleus basalis of Meynert (nbM), predicted the behavioral efficacy of chemogenetic inhibition in GTs. Furthermore, the total subregional transfection space, not transfection of just cholinergic neurons, correlated with performance effects. These results indicate that the cognitive-behavioral phenotype indexed by goal tracking, but not sign tracking, depends on activation of the basal forebrain-frontal cortical projection system and associated biases toward top-down or model-based performance.

The effects of stimulus pre-exposure and conditioning on overt visual attention.

Three experiments (a, b, c) combined to provide a well-powered examination of the effects of stimulus pre-exposure and conditioning on visual attention using an eye tracker and a space-shooter video game where a colored flashing light predicted an attacking spaceship. In each, group "control" received no pre-exposure to the light, group "same" received pre-exposure in the same context as conditioning, and group "different" received pre-exposure in a different context. Experiments differed in visual details regarding the game (1a vs. 1b and 1c) or minor details in the setup of the eye tracker (1a and 1b vs. 1c). Overall, pre-exposure retarded acquisition of keyboard responding. That effect was enhanced, rather than attenuated, by a context change. Separating participants by sign and goal trackers showed the context change enhanced the pre-exposure effect in goal trackers and reduced it in sign trackers. Visual attention to the light declined during pre-exposure and did not recover with either conditioning or a context switch. Visual attention to the light decreased during conditioning. Visual goal tracking toward where the spaceship would appear was also retarded with pre-exposure. Unlike the keyboard responding, a context change led to more normal goal-tracking acquisition. Results are discussed in terms of theories of attention and the potential effects of demand characteristics on the task. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Sign- and goal-tracking score does not correlate with addiction-like behavior following prolonged cocaine self-administration

RationaleIn classical conditioning, sign-tracking reflects behavior directed toward a conditioned stimulus (CS) in expectation of a reward (unconditioned stimulus, US); in contrast, goal-tracking describes behavior directed toward the location of delivery of a US. As cues previously paired with drugs of abuse promote drug-seeking and drug-taking behavior in both animals and humans and thus contribute to the severity of substance abuse, sign-tracking may represent a maladaptive cue-focused behavior that may increase addiction vulnerability as compared to goal-tracking. Recent studies do, in fact, support this possibility. Previous work in this area has focused primarily on paradigms using relatively limited exposure to drug rather than extended drug intake.ObjectivesHere, we used the DSM-IV–based 3-criteria (3-CRIT) model and examined whether a relationship exists between sign- or goal-tracking phenotypes and the prevalence of criteria associated with addiction-like behavior following extended cocaine self-administration as measured in this model.MethodsForty-six male Sprague Dawley rats underwent a Pavlovian conditioned approach (PCA) procedure and were characterized along a continuum as goal-trackers (GTs), intermediates (INTs), or sign-trackers (STs). The animals were subsequently trained to intravenous self-administer cocaine during 45 self-administration (SA) sessions and characterized for the 3 criteria outlined in the model: persistence of drug-seeking, motivation for cocaine-taking, and resistance to punishment.ResultsWe performed correlational analyses on the traits measured, finding no relationships between PCA score and addiction-like characteristics measured using the 3-CRIT model of addiction. However, STs showed significantly greater resistance to punishment than GTs.ConclusionsPhenotyping along a continuum of PCA scores may not be a valid predictor for identifying vulnerability to the addiction-like behaviors examined using the 3-CRIT model. However, PCA phenotype may predict a single feature of the 3-CRIT model, resistance to punishment, among those rats classified as either STs or GTs.

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.

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.

Repeated subcutaneous administration of PT150 has dose-dependent effects on sign tracking in male Japanese quail.

A devastating feature of drug dependence is the susceptibility of relapse (40-60%) after stretches of abstinence. In both animal and human research, it has been demonstrated that cues (e.g., levers, paraphernalia) associated with drug reward can instigate renewed drug taking. Research has shown animals that attend to a cue that predicts reward more than the location of reward delivery when the cue is present (sign trackers) have an increase in corticosterone (CORT), a primary stress hormone when compared with animals that do not sign track. This interaction of sign tracking and CORT implicate CORT's effects as a possible pharmacological target for cue-induced relapse behaviors. PT150 is a novel glucocorticoid receptor antagonist that reduces the effects of CORT. Previous research has shown that oral administration of 40 mg/kg PT150 reduced sign tracking. To better understand dose-dependent effects and to control for more accurate doses, the current experiment hypothesized that PT150 (20/40/60 mg/kg) given by subcutaneous (SC) injection to male quail would reduce sign tracking to a keylight conditional stimulus that predicts a grain unconditioned stimulus dose dependently. Results showed that SC injection of 20 mg/kg PT150 reduced sign tracking, but 40 or 60 mg/kg did not. The main findings from the current study are that the glucocorticoid receptor antagonist PT150 reduces sign tracking behavior dose dependently, and SC administration may provide better bioavailability compared with our previous study that used an oral route of administration. The current findings support previous literature by suggesting that the glucocorticoid receptor may be a potential pharmacological target for reducing relapse-like behaviors. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Sign Tracking and Goal Tracking Are Characterized by Distinct Patterns of Nucleus Accumbens Activity.

During Pavlovian conditioning, if a cue (e.g., lever extension) predicts reward delivery in a different location (e.g., a food magazine), some individuals will come to approach and interact with the cue, a behavior known as sign tracking (ST), and others will approach the site of reward, a behavior known as goal tracking (GT). In rats, the acquisition of ST versus GT behavior is associated with distinct profiles of dopamine release in the nucleus accumbens (NAc), but it is unknown whether it is associated with different patterns of accumbens neural activity. Therefore, we recorded from individual neurons in the NAc core during the acquisition, maintenance, and extinction of ST and GT behavior. Even though NAc dopamine is specifically important for the acquisition and expression of ST, we found that cue-evoked excitatory responses encode the vigor of both ST and GT behavior. In contrast, among sign trackers only, there was a prominent decrease in reward-related activity over the course of training, which may reflect the decreasing reward prediction error encoded by phasic dopamine. Finally, both behavior and cue-evoked activity were relatively resistant to extinction in sign trackers, as compared with goal trackers, although a subset of neurons in both groups retained their cue-evoked responses. Overall, the results point to the convergence of multiple forms of reward learning in the NAc.

Basal forebrain chemogenetic inhibition disrupts the superior complex movement control of goal-tracking rats.

Sign- and goal-tracking behavior signifies the influence of opposed cognitive-motivational styles, with the former being characterized by a tendency for approaching and contacting reward cues, including a readiness for attending, bottom-up, to salient cues, and a relatively greater vulnerability for developing and maintaining addiction-like behaviors. We previously demonstrated that these styles also impact the cognitive-motor interactions that are taxed during traversal of dynamic surfaces, with goal-trackers (GTs) making less movement errors and falling less frequently than sign-trackers (STs). The present experiment tested the hypothesis that complex movement control in GTs, but not STs, depends on activation of the basal forebrain projection system to telencephalic regions. Chemogenetic inhibition of the basal forebrain increased movement errors and falls in GTs during traversal of a rotating zigzag rod but had no significant effect on the relatively lower performance of STs. Neurochemical evidence confirmed the efficacy of the inhibitory designer receptor exclusively activated by designer drug (DREADD). Administration of clozapine-N-oxide (CNO) had no significant effect in GTs not expressing the DREADD. These results indicate that GTs, but not STs, activate the basal forebrain projection system to mediate their relatively superior ability for complex movement control. STs may also serve as an animal model in research on the role of basal forebrain systems in aging- and Parkinson's disease-associated falls. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A glucocorticoid receptor antagonist reduces sign-tracking behavior in male Japanese quail.

Addiction is characterized as a chronic debilitating disease. One devastating feature of addiction is the susceptibility of relapse (40-60%) after stretches of abstinence. One theory that may account for relapse suggests that drug cues (e.g., paraphernalia) may increase stress hormones, and this may prompt relapse. Repeatedly pairing a neutral cue with a reward is commonly utilized to measure what subjects learn about a cue that is predictive of reward. Research has shown that animals that attend to a cue more than to the reward (sign trackers) may be more vulnerable to drug addiction. Additionally, research has shown that sign tracking is associated with an increase in corticosterone, a primary stress hormone. PT150 is a novel glucocorticoid receptor antagonist that moderates the release of corticosterone. In the current experiment, it was hypothesized that subjects given repeated administration of PT150 would reduce sign tracking compared to subjects given placebo. Time spent (in seconds) near a cue that predicts reward (conditional stimulus) served as a measure of sign tracking, and PT150 or placebo was administered following sign tracking. An independent-samples t test revealed that subjects that received PT150 had reduced time spent near the conditioned stimulus compared to controls. Given the devastating effects of drug addiction, identification of a potential pharmacological intervention in the reduction of relapse would be of great value. Therefore, future research is needed to validate the use of PT150 in reducing behaviors associated with drug addiction. (PsycINFO Database Record

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

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. This study aimed to determine if inactivation of the PVT differentially mediates cue-induced drug-seeking behavior in sign-trackers and goal-trackers. Rats were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their Pavlovian conditioned approach behavior. Rats were then exposed to 15days 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. 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. 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.

Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity.

Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS+ and a DS-, respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS+ to reinstate cocaine seeking behavior. The DS+ was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS+ We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability.

Unresponsive Choline Transporter as a Trait Neuromarker and a Causal Mediator of Bottom-Up Attentional Biases.

Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.SIGNIFICANCE STATEMENT The vulnerability for addiction-like behavior has been associated with psychological traits, such as the propensity to attribute incentive salience to reward cues that is modeled in rats by sign-tracking behavior. Sign-trackers tend to approach and contact cues associated with reward, whereas their counterparts, the goal-trackers, have a preference for approaching the location of the reward. Here, we show that the capacity of presynaptic cholinergic synapses to respond to stimulation by elevating presynaptic choline uptake and releasing acetylcholine is attenuated in sign-trackers. Furthermore, pharmacological inhibition of choline transport induced sign-tracking behavior. Our findings suggest that reduced levels of cholinergic neuromodulation can mediate an attentional bias toward reward-related cues, thereby allowing such cues to exert relatively greater control over behavior.

The ability for cocaine and cocaine-associated cues to compete for attention

In humans, reward cues, including drug cues in individuals experiencing addiction, are especially effective in biasing attention towards them, so much so they can disrupt ongoing task performance. It is not known, however, whether this happens in rats. To address this question, we developed a behavioral paradigm to assess the capacity of an auditory drug (cocaine) cue to evoke cocaine-seeking behavior, thus distracting thirsty rats from performing a well-learned sustained attention task (SAT) to obtain a water reward. First, it was determined that an auditory cocaine cue (tone-CS) reinstated drug-seeking equally in sign-trackers (STs) and goal-trackers (GTs), which otherwise vary in the propensity to attribute incentive salience to a localizable drug cue. Next, we tested the ability of an auditory cocaine cue to disrupt performance on the SAT in STs and GTs. Rats were trained to self-administer cocaine intravenously using an Intermittent Access self-administration procedure known to produce a progressive increase in motivation for cocaine, escalation of intake, and strong discriminative stimulus control over drug-seeking behavior. When presented alone, the auditory discriminative stimulus elicited cocaine-seeking behavior while rats were performing the SAT, but it was not sufficiently disruptive to impair SAT performance. In contrast, if cocaine was available in the presence of the cue, or when administered non-contingently, SAT performance was severely disrupted. We suggest that performance on a relatively automatic, stimulus-driven task, such as the basic version of the SAT used here, may be difficult to disrupt with a drug cue alone. A task that requires more top-down cognitive control may be needed.

Can cleanerfish overcome temptation? A selective role for dopamine influence on cooperative-based decision making

Evidence suggests that animals are selected to make accurate choices and prioritize goals within the constraints of a given social environment to maximize fitness. These decisions are mostly based on complex processes in which value is linked to reward and cues may carry variable incentive salience. However, the level in which the incentive elicited by a cue is able to shift individual choices should differ between individuals and neurophysiological states. Here we used a notorious cooperative cleanerfish species Labroides dimidiatus to probe for differences in the incentive motivational valences given to food cues and then tested for the role of the dopaminergic system in the appraisal of such cues. We found that cleaners differed in Pavlovian conditioned approach behavioural responses to reward-associated stimuli: while the majority were fast to engage physically with the cue plate that indicated future reward delivery (sign trackers), only a few took significantly more time to respond (goal trackers). But amongst those that were considering the sole cue attractive, we discovered that the dopaminergic blockage decreased their initial propensity to approach and touch the cue plate. Our results show that dopamine disruption contributes to shifting the attribution of motivational incentive from the predictive cue towards the actual reward and provides key insight into the physiological framework of cooperative-based decision making.

Neural Activity in the Ventral Pallidum Encodes Variation in the Incentive Value of a Reward Cue.

There is considerable individual variation in the extent to which reward cues are attributed with incentive salience. For example, a food-predictive conditioned stimulus (CS; an illuminated lever) becomes attractive, eliciting approach toward it only in some rats ("sign trackers," STs), whereas others ("goal trackers," GTs) approach the food cup during the CS period. The purpose of this study was to determine how individual differences in Pavlovian approach responses are represented in neural firing patterns in the major output structure of the mesolimbic system, the ventral pallidum (VP). Single-unit in vivo electrophysiology was used to record neural activity in the caudal VP during the performance of ST and GT conditioned responses. All rats showed neural responses to both cue onset and reward delivery but, during the CS period, STs showed greater neural activity than GTs both in terms of the percentage of responsive neurons and the magnitude of the change in neural activity. Furthermore, neural activity was positively correlated with the degree of attraction to the cue. Given that the CS had equal predictive value in STs and GTs, we conclude that neural activity in the VP largely reflects the degree to which the CS was attributed with incentive salience. Cues associated with reward can acquire motivational properties (i.e., incentive salience) that cause them to have a powerful influence on desire and motivated behavior. There are individual differences in sensitivity to reward-paired cues, with some individuals attaching greater motivational value to cues than others. Here, we investigated the neural activity associated with these individual differences in incentive salience. We found that cue-evoked neural firing in the ventral pallidum (VP) reflected the strength of incentive motivation, with the greatest neural responses occurring in individuals that demonstrated the strongest attraction to the cue. This suggests that the VP plays an important role in the process by which cues gain control over motivation and behavior.

Sign Tracking, but Not Goal Tracking, is Resistant to Outcome Devaluation

During Pavlovian conditioning, a conditioned stimulus (CS) may act as a predictor of a reward to be delivered in another location. Individuals vary widely in their propensity to engage with the CS (sign tracking) or with the site of eventual reward (goal tracking). It is often assumed that sign tracking involves the association of the CS with the motivational value of the reward, resulting in the CS acquiring incentive value independent of the outcome. However, experimental evidence for this assumption is lacking. In order to test the hypothesis that sign tracking behavior does not rely on a neural representation of the outcome, we employed a reward devaluation procedure. We trained rats on a classic Pavlovian paradigm in which a lever CS was paired with a sucrose reward, then devalued the reward by pairing sucrose with illness in the absence of the CS. We found that sign tracking behavior was enhanced, rather than diminished, following reward devaluation; thus, sign tracking is clearly independent of a representation of the outcome. In contrast, goal tracking behavior was decreased by reward devaluation. Furthermore, when we divided rats into those with high propensity to engage with the lever (sign trackers) and low propensity to engage with the lever (goal trackers), we found that nearly all of the effects of devaluation could be attributed to the goal trackers. These results show that sign tracking and goal tracking behavior may be the output of different associative structures in the brain, providing insight into the mechanisms by which reward-associated stimuli—such as drug cues—come to exert control over behavior in some individuals.