A discrete cue associated with intravenous injections of cocaine acquires greater control over motivated behavior in some rats ('signtrackers', STs) than others ('goal-trackers', GTs). It is not known, however, if such variation generalizes to cues associated with other drugs. We asked, therefore, whether a discrete cue (a light) associated with the intravenous administration of an opioid drug (the shortacting mu receptor agonist, remifentanil) acquires incentive motivational properties differently in STs and GTs, as indicated by tests of Pavlovian conditioned approach and conditioned reinforcement. Consistent with studies using cocaine, STs approached a classically conditioned opioid cue more readily than GTs, and in a test of conditioned reinforcement worked more avidly to get it. Interestingly, STs and GTs did not differ in the acquisition of a conditioned orienting response. In addition, the performance of conditioned approach behavior, but not conditioned orientation, was attenuated by pretreatment with the dopamine receptor antagonist, flupenthixol, into the core of the nucleus accumbens. Lastly, food and opioid cues engaged similar amygdalo-striatal-thalamic circuitry to a much greater extent in STs than GTs, as indicated by Fos expression. Taken together, these data demonstrate that, similar to food and cocaine cues: (1) a discrete opioid cue attains greater incentive motivational value in STs than GTs; (2) the attribution of incentive motivational properties to an opioid cue is dopamine dependent; and (3) an opioid cue engages the so-called 'motive circuit' only if it is imbued with incentive salience.

Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. Recent evidence suggests that natural rewards may cause similar changes in the NAc, suggesting that drugs may activate mechanisms of plasticity shared with natural rewards, and allowing for unique interplay between natural and drug rewards. In this study, we demonstrate that sexual experience in male rats when followed by short or prolonged periods of loss of sex reward causes enhanced amphetamine reward, indicated by sensitized conditioned place preference for low-dose (0.5 mg/kg) amphetamine. Moreover, the onset, but not the longer-term expression, of enhanced amphetamine reward was correlated with a transient increase in dendritic spines in the NAc. Next, a critical role for the transcription factor ⌬FosB in sex experience-induced enhanced amphetamine reward and associated increases in dendritic spines on NAc neurons was established using viral vector gene transfer of the dominant-negative binding partner ⌬JunD. Moreover, it was demonstrated that sexual experience-induced enhanced drug reward, ⌬FosB, and spinogenesis are dependent on mating-induced dopamine D1 receptor activation in the NAc. Pharmacological blockade of D1 receptor, but not D2 receptor, in the NAc during sexual behavior attenuated ⌬FosB induction and prevented increased spinogenesis and sensitized amphetamine reward. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ⌬FosB and its downstream transcriptional targets.

The impact of the circadian timing system upon behavior and physiology is pervasive, and previous evidence suggests a circadian modulation of drug-seeking behavior and responsiveness to drugs of abuse. To further characterize daily rhythms in reward and to extend these observations to natural reinforcers, diurnal variation in the rewarding value of sex and systemic amphetamine was assessed via the conditioned place preference paradigm. To identify potential mechanisms for rhythmicity in reward, levels of tyrosine hydroxylase (TH) and core clock proteins (Period1 and Bmal1) were examined across the day in the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). During an initial training period, male rat sexual performance varied diurnally with a nadir near the light-to-dark transition. Diurnal rhythms also were evident for both mating and amphetamine-related reward. However, the rhythms for these particular stimuli exhibited differences in their pattern of timing, with sex reward showing a peak during the middark period and amphetamine reward exhibiting high points during the late night and midday with a nadir prior to the light-to-dark transition. A diurnal variation also was seen for the locomotor-activating effect of acute amphetamine administration with a peak during the late night. Western blot analyses revealed that Period1 and Bmal1 protein levels were rhythmic in the NAcc but not in the VTA. By contrast, TH protein levels were rhythmic in both the NAcc and VTA, but the peaks differed with that in the NAcc coinciding with the peak of sex reward and that in the VTA associated with the peak in amphetamine reward. Thus, it appears that both natural and drug-related reward vary in a diurnal fashion but differ in the timing of their peak and nadir levels. The phase relationships between reward rhythms and mesolimbic TH protein levels suggest that an increased capacity for the release of dopamine in the NAcc may underlie the rhythms in sex-related reward, while amphetamine-related reward occurs at a time when the likelihood of evoked NAcc DA release is relatively low.

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 ϩ and a DS Ϫ , 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 ϩ to reinstate cocaine seeking behavior. The DS ϩ 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 ϩ . We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.