Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity

Abstract

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⁺ and a DS^-, 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⁺ to reinstate cocaine seeking behavior. The DS⁺ 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⁺ We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability.

Keywords: acetylcholine; addiction; basal forebrain; drug cues; relapse; sign and goal trackers.

Figure 1.

Individual PCA index values across the five PCA training sessions for STs and GTs (data from rats eventually classified as intermediates are not shown). The final classification of the ST or GT phenotype (n = 19 and 17, respectively) was based on averaging PCA index values from PCA sessions 4 and 5. The predetermined PCA index score cutoffs for STs and GTs were 0.5 and −0.5, respectively.

Figure 2.

Measures of behavior toward a lever (CS; left column) versus the location of food delivery (food magazine or cup; right column) over the five PCA training sessions of rats that were eventually classified as STs (n = 19) or GTs (n = 17). The plots depict the mean ± SEM for the probability of approaching the lever CS during the 8 s CS period (a), the probability of approaching the food cup during the 8 s CS period (b), the number of lever contacts (c), the number of food cup entries during the 8 s CS period (d), latency to first lever contact after CS presentation (e), and the latency to the first food cup entry after CS presentation (f). STs increasingly and more rapidly contacted the CS (a, c, e), whereas GTs increasingly contacted the site of reward delivery (mgz., magazine; b, d, f).

Figure 3.

Acquisition of cocaine self-administration by STs (red; n = 19) and GTs (blue; n = 17) using an IC-based approach. Acquisition of self-administration did not differ between the phenotypes with respect to the number of responses (a) to the active (circles) or inactive (squares) ports and the number of cocaine infusion/min (b) for IC10, IC20, or IC40 (0.4 mg/kg/infusion; for results from LMM analyses, see Results).

Figure 4.

After animals learned to self-administer cocaine, they learned to self-administer cocaine in accordance with an IntA schedule. Both STs (n = 19) and GTs (n = 17) escalated cocaine intake over 14 IntA sessions, with STs having consumed a greater amount of cocaine across IntA training (a). Over 14 sessions, the difference between responses to the active port in the presence of the DS⁺ and the DS⁻ (filled symbols in b) increased at the same rate in STs and GTs. The difference between inactive responses in the presence of the DS⁺ and the DS⁻ remained near zero over sessions (open symbols in b; note that, for calculating these differences, the number of responses during the 25 min DS⁻ periods was divided by 5 to match the 5 min DS⁺ periods). By the end of IntA training (session #14), STs and GTs' cocaine consumption did not differ (c). d shows, for each block of session #14, the percentage active and inactive responses for the DS⁺ periods relative to the DS⁻ periods (resp, responses; act, active, inact, inactive; mean ± SEM). During DS⁺ periods, responses to the active, but not inactive, port were 500–2000% over DS⁻ periods, indicating that both STs and GTS effectively discriminated between the DS⁺ (drug available) and DS⁻ (no-drug available) periods (note that, for the calculation of the data in d, DS⁻ responses of zero were replaced by one).

Figure 5.

a, Initial extinction of drug-seeking behavior (no DS⁺, no cocaine) caused a decrease in the number of responses to the active and inactive nose port in both STs (n = 19) and GTs (n = 17). b, Three weeks after surgery (ST sham, n = 9; ST SAP, n = 10; GT sham, n = 9; GT SAP, n = 8), re-extinction again decreased the number of active responses in all groups (for LMM analyses, see Results).

Figure 6.

Number of responses to the active response port in the presence of the DS⁺ by sham-operated GTs (n = 9) and STs (n = 10) and rats with SAP-induced losses of the BF cholinergic system (STs, n = 9; GTs, n = 8). a, Number of active responses for sessions during which the DS⁺ was presented (right cluster of bars). In the presence of the DS⁺, sham-operated GTs generated more responses to the active response port than STs and deafferented GTs (see Results for ANOVA; multiple comparisons: *p < 0.05; **p < 0.01). Video-based analyses of a subset of rats for which videos were available (see Materials and Methods; ST sham, n = 5; ST SAP, n = 5; GT sham, n = 3; GT SAP, n = 6) further indicated that the relatively high levels of DS⁺-evoked active responses in sham-operated GTs observed throughout the session (a) occurred, although insignificantly, during the 4 s period after the onset of the DS⁺ (b) and, significantly, during the 26 s periods outside the presence of the DS⁺ (c). There were no significant effects of phenotype, SAP lesion, or of the interaction between the two factors on responses to the inactive port in either stimulus condition (see Results for ANOVA; data not shown). d, Number of orientation responses toward the DS⁺ relative to the total number of stimulus presentations during reinstatement sessions. Rats of both phenotypes and lesion status exhibited statistically similar orientation rates to the DS⁺. Compared with GTs with cholinergic losses and sham-operated STs, sham-operated GTs were >3 times more likely to exhibit a response to the active nose port if they exhibited an orientation response in that trial (see Results).

Figure 7.

ChAT-IR neurons on coronal sections from sham-operated (a–d) and SAP-lesioned (i–l) rats at AP levels −0.4, −0.9, −1.1, and −1.4 relative to bregma. Red arrows in b, j, and c indicate tracts produced by insertion of the infusion needle. The number of ChAT-IR neurons was estimated in two subregions of the basal forebrain: nbM and vbf (consisting of SI, MCPO, and HDB). Schematic drawings from each corresponding AP (middle column; e–h) illustrate the representative distribution of ChAT-IR neurons (blue dots) for sham-operated and the pattern of remaining neurons after SAP lesions (red dots; scale for all photomicrographs, in the bottom right corner in l:200 μm).

Figure 8.

Semiquantitative estimates of ChAT-IR neurons in the two subregions of the basal forebrain (nbM, vbf; see also Fig. 7) of sham-operated STs (filled red circles; a) and GTs (filled blue circles; b) and after infusions of the cholinotoxin SAP (empty red and blue circles in c, nbM, and d, vbf; ST sham: n = 10; GT sham: n = 9; ST SAP: n = 9; GT SAP: n = 8; AP levels: 1: −0.2 to −0.5 mm relative to bregma; 2: −0.6 to −0.9 mm; 3: −1.0 to −1.2 mm; 4: −1.3 to −1.5 mm]. Post hoc comparisons of main effects of AP level reflected in a that estimates at levels 1, 2, and 3 all differed from each other and in b that estimates at all levels differed from each other. For c, the results of post hoc comparisons of effects of AP levels are indicated (**p < 0.01, ***p < 0.001). A significant interaction between the effects of phenotype and AP levels on residual nbM neuron number estimates (c) reflected a lower number of residual cells at AP level 3 (p = 0.036) in STs compared with GTs.