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Background: Cognitive distortions regarding gambling outcomes confer vulnerability to pathological gambling. Using a rat slot machine task (rSMT), we previously demonstrated that the nonspecific D2 agonist quinpirole enhances erroneous expectations of reward on near-miss trials, suggesting a pivotal role for the D2 receptor family in mediating the near-miss effect. Identifying which receptor subtype is involved could facilitate treatment development for compulsive slot machine play. Methods: Thirty-two male Long Evans rats learned the rSMT. Three flashing lights could be set to on or off. A win was signaled if all three lights were set to on, whereas any other light pattern indicated a loss. Rats then chose between responding on the collect lever, which delivered 10 sugar pellets on win trials but a 10-second time penalty on loss trials, or to start a new trial instead. Performance was assessed following systemic administration of selective D2, D3, and D4 receptor ligands. Results: The selective D2 antagonist L-741,626, the D3 antagonist SB-277011-A, and the D3 agonist PD128,907 had no effect. In contrast, the selective D4 agonist PD168077 partially mimicked quinpirole’s effects, increasing erroneous collect responses on nonwin trials, whereas the D4 antagonist L-745,870 improved the error rate. L-745,870 was also the only antagonist that could attenuate the deleterious effects of quinpirole. Conclusions: The dopamine D4 receptor is critically involved in signaling reward expectancy in the rSMT. The ability of L-745,870 to reduce the classification of losses as wins suggests that D4 antagonists could be effective in treating problematic slot machine play. [Copyright &y& Elsevier]

Background: Dopaminergic activity plays a role in mediating the rewarding aspects of abused drugs, including nicotine. Nicotine modulates the reinforcing properties of other motivational stimuli, yet the mechanisms of this interaction are poorly understood. This study aimed to ascertain the impact of nicotine exposure on neuronal activity associated with reinforcing outcomes in dependent smokers. Methods: Smokers (n = 28) and control subjects (n = 28) underwent functional imaging during performance of a monetary incentive delay task. Using a randomized, counterbalanced design, smokers completed scanning after placement of a nicotine or placebo patch; nonsmokers were scanned twice without nicotine manipulation. In regions along dopaminergic pathway trajectories, we considered event-related activity for valence (reward/gain vs. punishment/loss), magnitude (small, medium, large), and outcome (successful vs. unsuccessful). Results: Both nicotine and placebo patch conditions were associated with reduced activity in regions supporting anticipatory valence, including ventral striatum. In contrast, relative to controls, acute nicotine increased activity in dorsal striatum for anticipated magnitude. Across conditions, anticipatory valence-related activity in the striatum was negatively associated with plasma nicotine concentration, whereas the number of cigarettes daily correlated negatively with loss anticipation activity in the medial prefrontal cortex only during abstinence. Conclusions: These data suggest a partial dissociation in the state- and trait-specific effects of smoking and nicotine exposure on magnitude- and valence-dependent anticipatory activity within discrete reward processing brain regions. Such variability may help explain, in part, nicotine''s impact on the reinforcing properties of nondrug stimuli and speak to the continued motivation to smoke and cessation difficulty. [Copyright &y& Elsevier]

Background: Recent evidence suggests an involvement of T-type calcium channels in the effects of drugs of abuse. Methods: We examined the influence of the novel, potent, and selective T-type calcium channel antagonist [2-(4-Cyclopropylphenyl)-N-((1R)-1-{5-[2,2,2-trifluoroethyl]oxo}pyridine-2-yl)ethyl]acetamide] (TTA-A2) (.3, 1, or 3 mg/kg) on motivation for nicotine, as measured by nicotine self-administration on a progressive ratio (PR) schedule, and nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine delivery (n = 11 or 12 Long Evans rats/group). Furthermore, we examined the specificity of the TTA-A2 effects by characterizing its influence on PR responding for food (in the absence or presence of nicotine-potentiated responding), food- versus nicotine-induced cue-potentiated reinstatement for a response previously reinforced by food administration (n = 11 or 12 Wistar Hannover rats/group), and its ability to induce a conditioned place aversion. Results: TTA-A2 dose-dependently decreased self-administration of nicotine on a PR schedule and the ability of both nicotine and a cue paired with nicotine to reinstate responding. The effects were specific for nicotine''s incentive motivational properties, as TTA-A2 did not influence responding for food on a PR schedule but did attenuate the ability of nicotine to potentiate responding for food. Likewise, TTA-A2 did not alter food-induced cue-potentiated reinstatement for a response previously reinforced by food but did decrease nicotine-induced cue-potentiated reinstatement. Finally, TTA-A2 did not produce an aversive state, as indicated by a lack of ability to induce conditioned place aversion. Conclusions: These data suggest that T-type calcium channel antagonists have potential for alleviating nicotine addiction by selectively decreasing the incentive motivational properties of nicotine. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Background: The death of an attachment figure triggers intrusive thoughts of the deceased, sadness, and yearning for reunion. Recovery requires reduction of symptoms. We hypothesized that symptoms might correlate with a capacity to regulate attention toward reminders of the deceased, and activity in, and functional connectivity between, prefrontal regulatory regions and the amygdala. Methods: Twenty recently bereaved subjects rated intrusive thoughts of the deceased versus a capacity to avoid thoughts (grief style). Reaction time was measured while subjects completed an Emotional Stroop (ES) task contrasting deceased-related with control words during functional magnetic resonance imaging (fMRI). Subjects subsequently visualized the death of the deceased and rated induced emotions. Results: Subjects demonstrated attentional bias toward deceased-related words. Bias magnitude correlated with amygdala, insula, dorsolateral prefrontal cortex (DLPFC) activity. Amygdala activity predicted induced sadness intensity. A double dissociation between grief style and both prefrontal and amygdala subregion activity was found. Intrusiveness correlated with activation of ventral amygdala and rostral anterior cingulate (rACC); avoidance correlated with deactivation of dorsal amygdala and DLPFC. A double dissociation between regulatory region and task-dependent functional connectivity (FC) was found. High DLPFC-amygdala FC correlated with reduced attentional bias, while low rACC-amygdala FC predicted sadness intensity. Conclusions: Results are consistent with a model in which activity in and functional connectivity between the amygdala and prefrontal regulatory regions indexes differences in mourners'' regulation of attention and sadness during pangs of grief, and may be used to distinguish between clinically relevant differences in grief style. [Copyright &y& Elsevier]

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 versus 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 toward and engagement with the CS itself. For other rats, the CS instead produced a “goal-tracking” CR: approach was directed away from the CS toward 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 versus incentive motivational functions and to study individual variation in the extent to which reward-associated stimuli act as incentive stimuli. [Copyright &y& Elsevier]