Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, whereby they themselves become attractive and desirable incentive stimuli. But individuals differ in whether a cue acts solely as a predictor that evokes a conditional response, or also serves as an incentive stimulus, and this determines the degree to which a cue might bias choice or even promote maladaptive behavior. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of reward learning in which “incentive salience” is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behavior. This work provides insight into the neurobiology of a form of reward learning that confers increased susceptibility to disorders of impulse control.

SummaryDrugs of abuse acquire different degrees of control over thoughts and actions based not only on the effects of drugs themselves, but also on predispositions of the individual. Those individuals who become addicted are unable to shift their thoughts and actions away from drugs and drug-associated stimuli. Thus in addicts, exposure to places or things (cues) that have been previously associated with drug-taking often instigates renewed drug-taking. We and others have postulated that drugassociated cues acquire the ability to maintain and instigate drug-taking behavior in part because they acquire incentive motivational properties through Pavlovian (stimulus-stimulus) learning. In the case of compulsive behavioral disorders, including addiction, such cues may be attributed with pathological incentive value ("incentive salience"). For this reason, we have recently begun to explore individual differences in the tendency to attribute incentive salience to cues that predict rewards. When discrete cues are associated with the non-contingent delivery of food or drug rewards some animals come to quickly approach and engage the cue even if it is located at a distance from where the reward will be delivered. In these animals the reward-predictive cue itself becomes attractive, eliciting approach towards it, presumably because it is attributed with incentive salience. Animals that develop this type of conditional response are called "sign-trackers". Other animals, "goal-trackers", do not approach the reward-predictive cue, but upon cue presentation they immediately go to the location where food will be delivered (the "goal"). For goal-trackers the reward-predictive cue is not attractive, presumably because it is not attributed with incentive salience. We review here preliminary data suggesting that these individual differences in the tendency to attribute incentive salience to cues predictive of reward may confer vulnerability or resistance to compulsive behavioral disorders, including addiction. It will be important, therefore, to study how environmental, neurobiological and genetic interactions determine the extent to which individuals attribute incentive value to reward-predictive stimuli.

Background If presentation of a stimulus (conditional stimulus, CS) reliably predicts delivery of a reward the CS will come to evoke a conditional response (CR) through Pavlovian learning, and the CS may also acquire incentive motivational properties. Thus, CSs can have both predictive and incentive properties. We ask here whether it is possible to dissociate the predictive vs. incentive properties of a CS in rats by considering individual differences in the nature of the CR. Methods We used Pavlovian procedures to study the ability of a localizable CS (an illuminated lever) to acquire two properties of an incentive stimulus - the ability to attract and the ability to act as a conditional reinforcer. Results For some rats the CS evoked a “sign-tracking” CR, consisting of approach towards and engagement with the CS itself. For other rats the CS instead produced a “goal-tracking” CR - approach was directed away from the CS towards the site of food delivery. For sign-trackers (but not goal-trackers) the CS also acted as an effective conditional reinforcer. Conclusions The predictive and incentive properties of a CS can be dissociated by considering individual differences in the CR. In a given animal a cue that is predictive of reward, supporting Pavlovian learning, may or may not be attributed with incentive salience. This procedure may provide a powerful means to test hypotheses regarding the role of neural systems in learning vs. incentive motivational functions, and to study individual variation in the extent to which reward-associated stimuli act as incentive stimuli.

Rats selectively-bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, while less impulsive on a measure of “impulsive choice”, bHRs were more impulsive on a measure of “impulsive action”— i.e. they had difficulty withholding an action in order to receive a reward, indicative of “behavioral disinhibition”. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2high receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine “release events” in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to “externalizing disorders” in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic “tone”.

If reward-associated cues acquire the properties of incentive stimuli they can come to powerfully control behavior, and potentially promote maladaptive behavior. Pavlovian incentive stimuli are defined as stimuli that have three fundamental properties: they are attractive, they are themselves desired, and they can spur instrumental actions. We have found, however, that there is considerable individual variation in the extent to which animals attribute Pavlovian incentive motivational properties (“incentive salience”) to reward cues. The purpose of this paper was to develop criteria for identifying and classifying individuals based on their propensity to attribute incentive salience to reward cues. To do this, we conducted a meta-analysis of a large sample of rats (N = 1,878) subjected to a classic Pavlovian conditioning procedure. We then used the propensity of animals to approach a cue predictive of reward (one index of the extent to which the cue was attributed with incentive salience), to characterize two behavioral phenotypes in this population: animals that approached the cue (“sign-trackers”) vs. others that approached the location of reward delivery (“goal-trackers”). This variation in Pavlovian approach behavior predicted other behavioral indices of the propensity to attribute incentive salience to reward cues. Thus, the procedures reported here should be useful for making comparisons across studies and for assessing individual variation in incentive salience attribution in small samples of the population, or even for classifying single animals.

These findings suggest that the development of approach behavior towards signals vs goal leads to distinct adaptations in the dopamine system. The sign-tracker vs goal-tracker phenotype may prove to be a valuable animal model to investigate individual differences in the way incentive salience is attributed to environmental stimuli, which may contribute to the development of addiction and other compulsive behavioral disorders.

Hippocampal glucocorticoid receptors (GR and MR) play an important role in glucocorticoid negative feedback. Abnormalities in negative feedback are found in depression and in post-traumatic stress disorder (PTSD), suggesting that GR and MR might be involved in the pathophysiology of these disorders. Enhanced negative feedback, the PTSD-specific neuroendocrine abnormality, can be induced in animals using a single prolonged stress (SPS) paradigm (a number of different stressors in one prolonged session, 'no stress' interval and a testing session one week later). In the current study, we examined hippocampal GR and MR mRNA distribution in the same animals that exhibited altered negative feedback following the SPS. Seven groups of adult Sprague-Dawley male rats (seven animals each) were used in two studies, comparing unstressed controls to acutely stressed animals (SPS: 24 h group), SPS animals (seven and 14 days), and SPS + chronic stress animals. GR and MR mRNA distribution across hippocampal subfields was studied using in-situ hybridization with 35S-labelled cRNA probes. Acute stress produced down-regulation of GR and MR mRNA across all hippocampal subfields. Seven days later (SPS-7 group), there was a differential recovery, with GR mRNA reaching higher than the prestress levels, and MR mRNA remaining down-regulated. The same differential regulation was present in the 14-day group. Chronically stressed animals that exhibited normal fast feedback also had normalization in their GR and MR mRNA levels. The MR/GR ratio was decreased only in animals that had enhanced fast feedback. These findings suggest that the increase in GR, in hippocampus is involved in the fast feedback hypersensitivity observed in the SPS animals, and might also underlie enhanced dexamethasone sensitivity found in PTSD. Since differential activation of GR and MR can modulate memory, behavioural responsivity, anxiety and fear, change in MR/GR ratio might also explain other PTSD-related phenomena.

When a discrete cue (a "sign") is presented repeatedly in anticipation of a food reward the cue can become imbued with incentive salience, leading some animals to approach and engage it, a phenomenon known as "sign-tracking" (the animals are sign-trackers; STs). In contrast, other animals do not approach the cue, but upon cue presentation go to the location where food will be delivered (the goal). These animals are known as goal-trackers (GTs). It has been hypothesized that individuals who attribute excessive incentive salience to reward-related cues may be especially vulnerable to develop compulsive behavioral disorders, including addiction. We were interested, therefore, in whether individual differences in the propensity to sign-track are associated with differences in responsivity to cocaine. Using an autoshaping procedure in which lever (conditioned stimulus) presentation was immediately followed by the response-independent delivery of a food pellet (unconditioned stimulus), rats were first characterized as STs or GTs and subsequently studied for the acute psychomotor response to cocaine and the propensity for cocaine-induced psychomotor sensitization. We found that GTs were more sensitive than STs to the acute locomotor activating effects of cocaine, but STs showed a greater propensity for psychomotor sensitization upon repeated treatment. These data suggest that individual differences in the tendency to attribute incentive salience to a discrete reward-related cue, and to approach and engage it, are associated with susceptibility to a form of cocaine-induced plasticity that may contribute to the development of addiction.