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Addiction is characterized by intermittent drug seeking despite rising costs. This behavior is heavily influenced by environmental stimuli that signal drug availability and reinforce seeking. We aimed to establish the relationship between three key aspects of human drug use in rats: the intermittent, binge nature of drug intake, the motivational conflict of drug seeking in the face of escalating negative costs, and the ability of different drug cues to interact to modulate relapse. Rats were trained to self administer cocaine on an intermittent access schedule, where brief drug availability states were signaled by a shift in the ambient lighting of the environment and cocaine delivery was signaled by a separate proximal cue. Rats then went through a conflict procedure, where foot shock intensity associated with cocaine seeking was escalated until intake was suppressed. We completed relapse tests where the drug delivery cue was non contingently presented alone, or in the context of dynamic drug availability state transitions. Intermittent access spurred psychomotor sensitization and binge-like cocaine intake. The intensity of binge-like drug taking during training was predictive of later drug seeking despite escalating costs. In relapse tests, the ability of a proximal drug cue to trigger relapse was gated by the presence of a global cue signaling drug-availability state transitions. Our results suggest that the pattern of drug intake plays a role in many features of addiction, including modifying an individual’s willingness to endure high costs associated with drug seeking. Further, our results indicate that drug-related sensory information can be hierarchically organized to exert a dynamic modulating influence on drug-seeking motivation.

RATIONALE: Addiction is characterized by intermittent drug seeking despite rising costs. This behavior is heavily influenced by environmental stimuli that signal drug availability and reinforce drug seeking. OBJECTIVE: To establish the relationship between three key aspects of human drug use in rats: the intermittent, binge nature of drug intake, the motivational conflict of drug seeking in the face of escalating negative costs, and the ability of different drug cues to interact to modulate relapse. METHODS: Male and female rats were trained to self-administer cocaine on an intermittent access schedule, where brief drug-availability states were signaled by a shift in the ambient lighting of the environment and cocaine infusions were signaled by a separate proximal discrete cue. Rats then went through a conflict procedure, where foot shock intensity associated with cocaine seeking was escalated until intake was suppressed. We then completed relapse tests where the drug-delivery cue was non contingently presented alone, or in the context of dynamic drug-availability state transitions. RESULTS: Intermittent access spurred psychomotor sensitization and binge-like cocaine intake. The intensity of binge-like drug taking during training was predictive of later drug seeking despite escalating costs during conflict. In relapse tests, the ability of a proximal discrete drug cue to trigger relapse was gated by the presence of a global cue signaling drug-availability state transitions. CONCLUSIONS: Our results suggest that the pattern of drug intake plays a role in many features of addiction, including modifying an individual’s willingness to endure high costs associated with drug seeking. Further, our studies indicate that drug-related sensory information can be hierarchically organized to exert a dynamic modulating influence on drug-seeking motivation.

The striatal dopamine system has long been studied in the context of reward learning, motivation, and movement. Given the prominent role dopamine plays in a variety of adaptive behavioral states, as well as diseases like addiction, it is essential to understand the full complexity of dopamine neurons and the striatal systems they target. A growing number of studies are uncovering details of the heterogeneity in dopamine neuron subpopulations. Here, we review that work to synthesize current understanding of dopamine system heterogeneity across three levels: anatomical organization, functions in behavior, and modes of action, wherein we focus on signaling profiles and local mechanisms for modulation of dopamine release. Together, these studies reveal new and emerging dimensions of the striatal dopamine system, informing its contribution to dynamic motivational and decision-making processes.

A recent Cell paper identifies a novel population of neurons within the ventral tegmental area producing the endogenous opioid nociceptin that regulates dopamine neuron firing and acts uniquely to gate motivation in reward seeking. These results highlight neuropeptidergic signaling as a critical component of functional heterogeneity in the midbrain.

Cognitive flexibility deficits are one of the most pervasive symptoms across psychiatric disorders, making continued investigation of the circuitry underlying this function a top priority. Medial septum (MS) lesions lead to perseverative, inflexible-type behavior; however, a role for this region in cognitive flexibility circuitry has never been examined. We activated the MS (DREADDs) and measured performance in a T-maze spatial reversal learning task in male Sprague–Dawley rats. Systemic activation of the MS (CNO) significantly decreased both trials to perform a reversal and entries into the previously baited arm. Intra-ventral subiculum CNO enhanced reversal learning in the same manner as systemic CNO and also significantly increased ventral tegmental area and decreased substantia nigra dopamine neuron population activity. Finally, co-injection of the D1 antagonist SCH23390 with CNO prevented the enhanced reversal learning performance seen in the previous two experiments. Taken together, these data suggest a key role for the MS in cognitive flexibility, and suggest that MS-mediated changes in midbrain dopamine neuron population activity could be one mechanism by which this occurs.

Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals towards the acquisition of “rewards” (i.e., food) that are necessary for survival. Here, we test the fundamental role of midbrain dopamine neurons in conferring predictive and motivational properties to cues, independent of external rewards. We demonstrate that brief phasic optogenetic excitation of dopamine neurons, when presented in temporal association with discrete sensory cues, is sufficient to instantiate those cues as conditioned stimuli that subsequently both evoke dopamine neuron activity on their own, and elicit cue-locked conditioned behavior. Critically, we identify highly parcellated functions for dopamine neuron subpopulations projecting to different regions of striatum, revealing dissociable dopamine systems for the generation of incentive value and conditioned movement invigoration. These results show that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to create, gate, and shape cue-controlled behaviors.

Although post-traumatic stress disorder (PTSD) and addiction are very different disorders, both are characterized by hyperreactivity to trauma- or drug-related cues, respectively. We investigated whether an appetitive conditioning task, Pavlovian conditioned approach, which predicts vulnerability to reinstatement of cocaine-seeking, also predicts fear incubation, which may be a marker for vulnerability to PTSD. We classified rats based on whether they learned to approach and interact with a food predictive cue (sign-trackers), or, whether upon cue presentation they went to the location of impending food delivery (goal-trackers). Rats were then exposed to extensive Pavlovian tone-shock pairings, which causes the fear response to increase or “incubate” over time. We found that the fear incubation effect was only present in sign-trackers. The behavior of goal-trackers was more consistent with a normal fear response – it was most robust immediately after training and decayed slowly over time. Sign-trackers also had lower levels of brain-derived neurotrophic factor (BDNF) protein in the prefrontal cortex than goal-trackers. These results indicate that, while many factors likely contribute to the disproportionate co-occurrence of PTSD and substance abuse, one such factor may be a core psychological trait that biases some individuals to attribute excessive motivational significance to predictive cues, regardless of the emotional valence of those cues. High levels of BDNF in the prefrontal cortex may be protective against developing excessive emotional and motivational responses to salient cues.

Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals towards the acquisition of “rewards” (i.e., food) that are necessary for survival. Here, we test the fundamental role of midbrain dopamine neurons in conferring predictive or motivational properties to cues, independent of external rewards. We demonstrate that phasic optogenetic excitation of dopamine neurons throughout the midbrain, when presented in temporal association with discrete sensory cues, is sufficient to instantiate those cues as conditioned stimuli that subsequently both evoke dopamine neuron activity on their own, and elicit cue-locked conditioned behaviors. Critically, we identify highly parcellated behavioral functions for dopamine neuron subpopulations projecting to discrete regions of striatum, revealing dissociable mesostriatal systems for the generation of incentive value and movement invigoration. These results show that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to shape cue-controlled behavior.

Cues associated with rewards, such as food or drugs of abuse, can themselves acquire motivational properties. Acting as incentive stimuli, such cues can exert powerful control over motivated behavior, and in the case of cues associated with drugs, they can goad continued drug-seeking behavior and relapse. However, recent studies reviewed here suggest that there are large individual differences in the extent to which food and drug cues are attributed with incentive salience. Rats prone to approach reward cues (sign-trackers) attribute greater motivational value to discrete localizable cues and interoceptive cues than do rats less prone to approach reward cues (goal-trackers). In contrast, contextual cues appear to exert greater control over motivated behavior in goal-trackers than sign-trackers. It is possible to predict, therefore, before any experience with drugs, in which animals specific classes of drug cues will most likely reinstate drug-seeking behavior. The finding that different individuals may be sensitive to different triggers capable of motivating behavior and producing relapse suggests there may be different pathways to addiction, and has implications for thinking about individualized treatment. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

When exposed to the sights, sounds, smells and/or places that have been associated with rewards, such as food or drugs, some individuals have difficulty resisting the temptation to seek out and consume them. Others have less difficulty restraining themselves. Thus, Pavlovian reward cues may motivate maladaptive patterns of behavior to a greater extent in some individuals than in others. We are just beginning to understand the factors underlying individual differences in the extent to which reward cues acquire powerful motivational properties, and therefore, the ability to act as incentive stimuli. Here we review converging evidence from studies in both human and non-human animals suggesting that a subset of individuals are more “cue reactive”, in that certain reward cues are more likely to attract these individuals to them and motivate actions to get them. We suggest that those individuals for whom Pavlovian reward cues become especially powerful incentives may be more vulnerable to impulse control disorders, such as binge eating and addiction.

The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction-error signal necessary for stimulus–reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value (‘incentive salience’) to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of Pavlovian-conditioned approach behavior – one in which the cue acquires powerful motivational properties (sign-tracking) and another closely related one in which it does not (goaltracking). After acquisition of these conditioned responses (CRs), intra-accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign-tracking CR, but not a goal-tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction-like decline in behavior, but maximally impaired expression of a sign-tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction-error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus–reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties.

Animals vary considerably in the degree to which they attribute incentive salience to cues predictive of reward. When a discrete cue (conditional stimulus) is repeatedly paired with delivery of a food reward (unconditional stimulus) only some rats ("sign-trackers"; STs) come to find the cue itself an attractive and desirable incentive stimulus. For other rats ("goal-trackers"; GTs) the cue is an effective conditional stimulus - it evokes a conditional response - but it is less attractive and less desirable. Given that STs have particular difficulty resisting reward cues, and are thought to have poor inhibitory control over their behavior, we hypothesized that they may also be more impulsive. There are, however, multiple forms of impulsivity; therefore, we compared STs and GTs on two tests of so-called impulsive action - a 2-choice serial reaction time task and a differential reinforcement of low rates of responding task, and one test of impulsive choice - a delay discounting choice procedure. We found that relative to GTs, STs were more impulsive on the two tests of impulsive action, but not on the test of impulsive choice. We speculate that when these two traits combine, that is, when an individual is not only prone to attribute incentive salience to reward cues but also prone to impulsive action, they may be especially susceptible to impulse control disorders, including addiction.

Background In addicts drug cues attract attention, elicit approach, and motivate drug-seeking and drug-taking behavior, and addicts find it difficult to resist such cues. In preclinical studies we have found, however, that food cues acquire incentive motivational properties only in a subset of individuals. For example, a food cue becomes attractive, eliciting approach and engagement with it, and acts as an effective conditional reinforcer in some rats but not others. We asked, therefore, whether rats that have a propensity to attribute incentive salience to a food cue are the same ones that attribute incentive value to a drug (cocaine) cue. Methods We first used a Pavlovian conditioned approach procedure to determine which individual rats attributed incentive salience to a food cue. A second cue was then associated with the IV self-administration of cocaine. Later, the ability of the cocaine cue to maintain self-administration behavior and to reinstate self-administration after extinction was assessed. Results We report that in individuals that had a propensity to attribute incentive salience to a food cue, a cocaine cue spurred motivation to take drugs (its removal greatly diminished self-administration) and reinstated robust drug-seeking after extinction. However, in those individuals that failed to attribute incentive salience to a food cue, the cocaine cue was relatively devoid of incentive motivational properties. Conclusions We conclude that it is possible to determine, before any drug experience, which individuals will most likely have difficulty resisting drug cues, a trait that might confer susceptibility to addiction.

Tying complex psychological processes to precisely defined neural circuits is a major goal of systems and behavioural neuroscience. This is critical for understanding adaptive behaviour, and also how neural systems are altered in states of psychopathology, such as addiction. Efforts to relate psychological processes relevant to addiction to activity within defined neural circuits have been complicated by neural heterogeneity. Recent advances in technology allow for manipulation and mapping of genetically and anatomically defined neurons, which when used in concert with sophisticated behavioural models, have the potential to provide great insight into neural circuit bases of behaviour. Here we discuss contemporary approaches for understanding reward and addiction, with a focus on midbrain dopamine and cortico-striato-pallidal circuits.

Successful reward seeking requires the interaction of multiple psychological processes, including learning (i.e., creating connections between actions/stimuli and rewarding outcomes), motivation (i.e., wanting to obtain rewarding outcomes), and affect (i.e., liking rewarding outcomes). There are two

Addiction is characterized by a high propensity for relapse, in part because cues associated with drugs can acquire Pavlovian incentive motivational properties, and acting as incentive stimuli, such cues can instigate and invigorate drug-seeking behavior. There is, however, considerable individual variation in the propensity to attribute incentive salience to reward cues. Discrete and localizable reward cues act as much more effective incentive stimuli in some rats (‘sign-trackers', STs), than others (‘goal-trackers', GTs). We asked whether similar individual variation exists for contextual cues associated with cocaine. Cocaine context conditioned motivation was quantified in two ways: (1) the ability of a cocaine context to evoke conditioned hyperactivity and (2) the ability of a context in which cocaine was previously self-administered to renew cocaine-seeking behavior. Finally, we assessed the effects of intra-accumbens core flupenthixol, a nonselective dopamine receptor antagonist, on context renewal. In contrast to studies using discrete cues, a cocaine context spurred greater conditioned hyperactivity, and more robustly renewed extinguished cocaine seeking in GTs than STs. In addition, cocaine context renewal was blocked by antagonism of dopamine receptors in the accumbens core. Thus, contextual cues associated with cocaine preferentially acquire motivational control over behavior in different individuals than do discrete cues, and in these individuals the ability of a cocaine context to create conditioned motivation for cocaine requires dopamine in the core of the nucleus accumbens. We speculate that different individuals may be preferentially sensitive to different ‘triggers' of relapse.

Drug addiction is characterized by persistent, maladaptive drug-seeking behavior and a high propensity for relapse after abstinence. Laboratory studies suggest that this phenotype can be attributed to impaired reward learning and decision making, coupled with exaggerated incentive motivation for drugs and drug-associated stimuli (1,2). Drug-induced plasticity in mesocorticostriatal circuits is thought to underlie these behavioral changes, with the nucleus accumbens in particular being a prominent node within the system for integrating learning and motivational information. Although much research has been done, important questions remain with regard to which specific facets of learning and motivation are altered by exposure to drugs of abuse and if drug-induced alterations in information processing in the accumbens are causal to these changes in behavior. A new study (3) sheds light on this important issue. In the current issue, Saddoris and Carelli (3) show that rats with a history of past cocaine self-administration exhibit normal learning, relative to saline-treated rats, in a simple first-order Pavlovian discrimination task, where a conditioned stimulus (CS ) was paired with food, whereas another cue had no associated outcome. Critically, cocaine-experienced rats failed to learn a second-order Pavlovian association, when a new cue (secondorder cue [SOC ]) predicted the original CS in the absence of food itself. The deficit in second-order conditioning exhibited by cocaine-experienced rats was associated with reduced neural activity within the nucleus accumbens in response to the SOC . Saline-treated rats readily learned this second-order association, and neurons within the nucleus accumbens of these subjects encoded the SOC . Thus, the current results suggest that cocaine experience might preferentially impair learning of new, higherorder associations, and these deficits are related to a lack of taskrelevant neural encoding within the nucleus accumbens. The results of Saddoris and Carelli (3) provide an extension of recent findings [reviewed in (4)] demonstrating that, after cocaine exposure, rats can learn simple Pavlovian cue discriminations but show dramatic deficits in reversal learning, another form of higher-order learning that requires shifting strategies to obtain reward. Impairments in reversal learning are associated with disrupted cue-outcome encoding dynamics within the basolateral amygdala (BLA) and prefrontal cortical regions like the orbitofrontal cortex (OFC). As a consequence of learning cue discriminations, some neurons in the BLA and OFC develop reward cueselective firing patterns that normally switch cue preference when the rewarded cue is changed in the reversal phase. In cocainetreated rats, however, this reward cue-selective activity fails to

Even when trained under exactly the same conditions outbred male Sprague-Dawley (SD) rats vary in the form of the Pavlovian conditioned approach response (CR) they acquire. The form of the CR (i.e. sign-tracking vs. goal-tracking) predicts to what degree individuals attribute incentive salience to cues associated with food or drugs. However, we have noticed variation in the incidence of these two phenotypes in rats obtained from different vendors. In this study, we quantified sign- and goal-tracking behavior in a reasonably large sample of SD rats obtained from two vendors (Harlan or Charles River), as well as from individual colonies operated by both vendors. Our sample of rats acquired from Harlan had, on average, more sign-trackers than goal-trackers, and vice versa for our sample of rats acquired from Charles River. Furthermore, there were significant differences among colonies of the same vendor. Although it is impossible to rule out environmental variables, SD rats at different vendors and barriers may have reduced phenotypic heterogeneity as a result of genetic variables, such as random genetic drift or population bottlenecks. Consistent with this hypothesis, we identified marked population structure among colonies from Harlan. Therefore, despite sharing the same name, investigators should be aware that important genetic and phenotypic differences exist among SD rats from different vendors or even from different colonies of the same vendor. If used judiciously this can be an asset to experimental design, but it can also be a pitfall for those unaware of the issue.

Although fear directs adaptive behavioral responses, how aversive cues recruit motivational neural circuitry is poorly understood. Specifically, while it is known that dopamine (DA) transmission within the nucleus accumbens (NAc) is imperative for mediating appetitive motivated behaviors, its role in aversive behavior is controversial. It has been proposed that divergent phasic DA transmission following aversive events may correspond to segregated mesolimbic dopamine pathways; however, this prediction has never been tested. Here, we used fast-scan cyclic voltammetry to examine real-time DA transmission within NAc core and shell projection systems in response to a fear-evoking cue. In male Sprague Dawley rats, we first demonstrate that a fear cue results in decreased DA transmission within the NAc core, but increased transmission within the NAc shell. We examined whether these changes in DA transmission could be attributed to modulation of phasic transmission evoked by cue presentation. We found that cue presentation decreased the probability of phasic DA release in the core, while the same cue enhanced the amplitude of release events in the NAc shell. We further characterized the relationship between freezing and both changes in DA as well as local pH. Although we found that both analytes were significantly correlated with freezing in the NAc across the session, changes in DA were not strictly associated with freezing while basic pH shifts in the core more consistently followed behavioral expression. Together, these results provide the first real-time neurochemical evidence that aversive cues differentially modulate distinct DA projection systems.

The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction-error signal necessary for stimulus-reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value ('incentive salience') to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of pavlovian-conditioned approach behavior--one in which the cue acquires powerful motivational properties (sign-tracking) and another closely related one in which it does not (goal-tracking). After acquisition of these conditioned responses (CRs), intra-accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign-tracking CR, but not a goal-tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction-like decline in behavior, but maximally impaired expression of a sign-tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction-error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus-reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties.

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.

Cues in the environment associated with drug use draw the attention of addicts, elicit approach, and motivate drug-seeking and drug-taking behavior, making abstinence difficult. However, preclinical studies have identified large individual differences in the extent to which reward cues acquire these incentive motivational properties. For example, only in some rats does a spatially discrete food cue become attractive, eliciting approach and engagement with it, and acts as an effective conditioned reinforcer. Moreover, a discrete cocaine cue also acquires greater motivational control over behavior in rats prone to attribute incentive salience to a food cue. In this study, we asked whether there is similar individual variation in the extent to which interoceptive cues produced by cocaine itself instigate cocaine-seeking behavior. After quantifying individual variation in the propensity to attribute incentive salience to a food cue, rats were trained to self-administer cocaine in the absence of an explicit conditional stimulus. We then assessed motivation for cocaine by: (1) performance on a progressive ratio schedule, and (2) the degree to which a cocaine 'prime' reinstated cocaine-seeking following extinction of self-administration behavior. We found that rats prone to attribute incentive salience to a food cue worked harder for cocaine, and showed more robust cocaine-induced reinstatement. We conclude that there is considerable individual variation in the motivational properties of cocaine itself, and this can be predicted by the propensity to attribute incentive salience to reward cues.

Delay to presentation is one variable that can weaken the reinforcing efficacy of an outcome in a choice situation and drugs have been shown to modify such choices. A growing body of literature has examined effects of stimulant drugs on temporal (delay) discounting, but effects of caffeine, the most widely used stimulant in the world, have not previously been assessed. In the present experiment, effects of caffeine (administered acutely and repeatedly) on temporal discounting were analyzed. Male Sprague–Dawley rats (n = 7) chose between a single food pellet delivered immediately after a lever press and three food pellets delivered after a delay. The delay to the three pellets increased within each session, from 0 to 16 s. High doses of caffeine increased large-reinforcer choice relative to control conditions. With repeated caffeine exposure, percent choice for the large reinforcer decreased relative to acute administration, but was still greater than pre-drug baseline. Following withdrawal of drug administration, choice returned to levels seen during pre-drug baseline. Reintroduction of caffeine increased the percent choice for a larger, delayed reinforcer to near acute levels. The results from the present study are consistent with previous research in which stimulant drugs have decreased temporal (delay) discounting.

Cues associated with drug use attract the attention of addicts, draw them to locations where drugs are located, and motivate drug-seeking—often leading to relapse—even in the face of an expressed desire to remain abstinent. There is, however, considerable individual variation in the ability of reward cues to gain motivational control over behavior. Emerging evidence from preclinical studies suggests that such variation is due, at least in part, to intrinsic differences in the extent to which reward cues are attributed with incentive salience, thereby acquiring the properties of incentive stimuli. When a Pavlovian conditional stimulus (CS) reliably predicts delivery of a food reward, for some rats (sign-trackers; STs), the CS itself becomes attractive, in that these rats approach and interact with the CS, and becomes ‘wanted', in that these rats will work just to obtain the CS. For other rats (goal-trackers; GTs), the CS itself is not attractive, but instead evokes conditioned approach towards the location of food delivery (rather than the CS), and GTs will not work avidly to get the CS (Meyer et al, 2012). Importantly, variation in the propensity to attribute incentive salience to a food cue predicts the extent to which drug cues gain motivational control over behavior. For example, a cocaine-associated cue is more effective in maintaining self-administration behavior, and instigates more robust relapse behavior, in STs than GTs (Saunders and Robinson, 2010). Additionally, STs will exert more effort to self-administer cocaine, and are more likely to relapse when ‘primed' with drugs themselves (Saunders and Robinson, 2011). Therefore, it is possible to predict, before any drug experience, which rats will find drug cues more desirable, will exhibit greater motivation to take drugs, and will be more likely to relapse. Thus, the extent to which drugs cues acquire motivational properties may not only influence their ability to control normal behavior but to also tempt maladaptive behavior, thereby contributing to addiction vulnerability. Several lines of evidence suggest that the propensity to attribute incentive salience to reward cues represents a complex psychological trait (Meyer et al, 2012). First, there are neurobiological differences between STs and GTs, including differences in dopaminergic systems (Flagel et al, 2011; Flagel et al, 2010). Second, the variation is heritable (Flagel et al, 2010), indicating that some unknown genetic differences contribute to variation in reward cue processing. Third, the extent to which rats become STs or GTs is influenced by early life experiences (Lomanowska et al, 2011), suggesting that environmental factors also contribute to how individuals process and respond to reward cues in adulthood. In conclusion, this line of research provides a novel approach to understanding the interplay between genetic, epigenetic, environmental, and neural-systems-level factors that confer susceptibility (and resilience) to impulse-control disorders, such as addiction. Implications for the development of clinical intervention strategies include: (1) greater attention to individual differences in the psychological factors that control pathological motivation for drugs, and (2) greater recognition that, in susceptible individuals, drug cues may be especially insidious in instigating and maintaining drug-seeking behavior.

The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.