Cue-evoked cocaine "craving": role of dopamine in the accumbens core

Abstract

Drug-associated cues can acquire powerful motivational control over the behavior of addicts, and can contribute to relapse via multiple, dissociable mechanisms. Most preclinical models of relapse focus on only one of these mechanisms: the ability of drug cues to reinforce drug-seeking actions following a period of extinction training. However, in addicts, drug cues typically do not follow seeking actions; they precede them. They often produce relapse by evoking a conditioned motivational state ("wanting" or "craving") that instigates and/or invigorates drug-seeking behavior. Here we used a conflict-based relapse model to ask whether individual variation in the propensity to attribute incentive salience to reward cues predicts variation in the ability of a cocaine cue to produce conditioned motivation (craving) for cocaine. Following self-administration training, responding was curtailed by requiring rats to cross an electrified floor to take cocaine. The subsequent response-independent presentation of a cocaine-associated cue was sufficient to reinstate drug-seeking behavior, despite the continued presence of the adverse consequence. Importantly, there were large individual differences in the motivational properties of the cocaine cue, which were predicted by variation in the propensity to attribute incentive salience to a food cue. Finally, a dopamine antagonist injected into the nucleus accumbens core attenuated, and amphetamine facilitated, cue-evoked cocaine seeking, implicating dopamine signaling in cocaine cue-evoked craving. These data provide a promising preclinical approach for studying sources of individual variation in susceptibility to relapse due to conditioned craving and implicate mesolimbic dopamine in this process.

Figure 1.

Diagram comparing reinstatement procedures. A, Traditional extinction-reinstatement procedure. Typically in these studies, rats are trained to self-administer cocaine paired with a discrete visual cue (left). Following acquisition of stable self-administration, extinction training commences, where actions have no consequences. Rats initially respond at a high rate (second panel), but eventually learn that cocaine is no longer available and stop responding (third panel). During the reinstatement test, drug-seeking actions produce the cocaine-paired cue only (right), which promotes a new high level of responding. B, Conflict-based relapse model. Rats are first trained to self-administer cocaine paired with a discrete visual cue, as in A (left). Following the acquisition of stable self-administration, the front two-thirds of the chamber floor is electrified with constant current. Initially, footshock is applied at a low intensity, and rats continue to self-administer cocaine (second panel). Footshock intensity is then gradually escalated, resulting in a near-complete discontinuation of cocaine self-administration (third panel) despite continued drug availability. During the reinstatement test, the cocaine-paired cue is presented intermittently throughout the session and independent of the animal's behavior. The ability of the cue to spur a rat to cross the electrified floor to make drug-seeking responses, which now have no consequences, is quantified (right). This conflict procedure was based on Cooper et al. (2007), although in that study an action also produced the cue (i.e., the cue could also act as a conditioned reinforcer), which was not the case here.

Figure 2.

Individual variation in PCA behavior. PCA index scores for individual rats from the PAIRED groups in Experiment 1 were calculated, as described in the Materials and Methods, and are plotted. Rats receiving a score between 1.0 and 0.25 were classed as STs, those with a score between 0.24 and −0.24 were classed as INs, and those with a score between −0.24 and −1.0 were classed as GTs.

Figure 3.

Acquisition of cocaine (0.4 mg/kg/infusion) self-administration behavior in PAIRED STs (n = 10) and GTs (n = 10) in Experiment 1. A, The average number of active and inactive nose-poke responses made at ICs 10, 20, and 40. B, The average cumulative interinfusion interval during the last two self-administration sessions at IC 40. Symbols represent the means ± SEM. Infs, Infusions.

Figure 4.

Self-administration in the face of an adverse consequence (Experiment 1). A, Average number of cocaine infusions taken at escalating footshock intensities for PAIRED STs (n = 10) and GTs (n = 10), and total infusions taken (inset) in Experiment 1. B, Average final footshock intensity reached per group. Symbols represent the means ± SEM. ns, Not significant (at p < 0.05); mA, milliamps.

Figure 5.

Individual variation in cue-evoked reinstatement. A, Average total active nose pokes made during the 30 min reinstatement test for PAIRED STs (n = 10) and GTs (n = 10) in Experiment 1. Dashed lines within the bars represent inactive nose pokes. B, Total number of active responses made during the reinstatement test for each PAIRED rat in Experiment 1, as a function of PCA index score. Note that INs (n = 8) were included here to illustrate the relationship across the entire distribution of PCA scores. C, Average total active nose pokes made during the 30 min reinstatement test for UNPAIRED STs (n = 8) and GTs (n = 7) in Experiment 1. Dashed lines represent inactive nose pokes. D, Total number of active responses made during the reinstatement test for each UNPAIRED rat in Experiment 1, as a function of PCA index score. UNPAIRED INs (n = 7) are shown to illustrate the relationship across the entire PCA score range. Symbols represent the means ± SEM. **p < 0.01. ns, Not significant (at p > 0.05).

Figure 6.

Cue-evoked versus uncued reinstatement in PAIRED STs. Average total active nose pokes made during the 30 min reinstatement test for PAIRED STs that received noncontingent cue presentations during reinstatement (n = 10) and PAIRED STs that did not receive cue presentations during reinstatement (n = 7). Dashed lines represent inactive nose pokes. Symbols represent the means ± SEM. *p < 0.05.

Figure 7.

Individual variation in cue-evoked reinstatement—noncontingent cocaine cue responses. A, Average active nose pokes made during noncontingent cocaine cue presentations (CS active responses) in the 30 min reinstatement test for PAIRED STs (n = 10) and GTs (n = 10) in Experiment 1. B, Active responses made during noncontingent cue presentations for each PAIRED rat in Experiment 1, as a function of PCA index score. C, Average active nose pokes made during noncontingent cue presentations for UNPAIRED STs (n = 8) and GTs (n = 7) in Experiment 1. D, Active responses made during noncontingent cue presentations for each UNPAIRED rat in Experiment 1, as a function of PCA index score. Symbols represent the means ± SEM. *p < 0.05. ns, Not significant (at p > 0.05).

Figure 8.

Distribution of active responses for PAIRED STs. Left pie chart, Breakdown of the percentage of the reinstatement session during which the cue was present (cued) versus the no-cue period. Right pie chart, The percentage of total active responses made by PAIRED STs in cue versus no-cue periods during the reinstatement test session.

Figure 9.

Effect of accumbens core dopamine receptor blockade on individual variation in cue-evoked reinstatement. A, Average total active responses made for rats that received either vehicle or flupenthixol (20 μg) in the nucleus accumbens core before the reinstatement test. B, Average number of active responses made during CS periods in the reinstatement test for vehicle- and flupenthixol-treated rats. C, Location of microinjection tips within the nucleus accumbens core relative to bregma for flupenthixol and vehicle rats. Symbols represent the means ± SEM. *p < 0.05.

Figure 10.

Effect of intra-accumbens core amphetamine on individual variation in cue-evoked reinstatement. A, Average total active responses made during the reinstatement test for rats treated with vehicle or amphetamine (10 μg) in the nucleus accumbens core. B, Average CS active responses for vehicle- and amphetamine-treated rats. C, Location of microinjection tips within the nucleus accumbens core relative to bregma for amphetamine and vehicle rats (note: vehicle placements shown here are the same as in Fig. 9C). Symbols represent the means ± SEM. *p < 0.05.