Reinstatement of MDMA (ecstasy) seeking by exposure to discrete drug-conditioned cues

Abstract

The widely used recreational drug MDMA (ecstasy) supports self-administration in animals, but it is not known whether MDMA-associated cues are able to reinstate drug seeking in a relapse model of drug addiction. To assess this possibility, drug-naïve rats were trained to press a lever for MDMA infusions (0.30 mg/kg/infusion, i.v.) paired with a compound cue (light and tone) in daily 2 h sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. Conditioned cue-induced reinstatement tests were conducted after lever pressing was extinguished in the absence of MDMA and the conditioned cues. Conditioned cues reinstated lever pressing after extinction, and the magnitude of reinstatement was positively correlated with the level of responding during MDMA self-administration. These results show for the first time that conditioned cues can trigger reinstatement of MDMA-seeking behavior in rats, and that individual differences in the pattern of MDMA self-administration can predict the magnitude of reinstatement responding.

Figure 1

(A) Mean lever presses for each of 14 daily 2-hr MDMA self-administration sessions. Rats (n = 7) were responding for intravenous infusions of 0.075 mg of MDMA on a modified FR5 schedule of reinforcement. Error bars represent S.E.M. (B) Mean lever presses during CS-induced reinstatement session (CS) compared to the prior extinction session (EXT). Extinction and reinstatement sessions were 1 hr in length. CS-induced reinstatement sessions began with an initial non-contingent presentation of the CS; thereafter, responding was reinforced only by the CS contingent upon an FR1 schedule of reinforcement. Following any 10-min time interval without a lever press, an additional non-contingent CS was presented. Error bars represent S.E.M. * p < 0.05 compared to prior extinction session. (C and D) Raster displays of lever pressing in two rats with different rates and patterns of responding. Each short vertical line above the time axis represents a lever press. Labels to the left of the raster indicate self-administration day (1–14) and extinction session (EXT) prior to CS-induced reinstatement session (CS). The thick vertical lines mark the end of extinction and reinstatement sessions.

Figure 2

Regression slope for the correlation between MDMA self-administration and CS-induced responding in individual rats. There was a very strong positive correlation between the response rate of rats during the last self-administration session and their total presses during CS-induced reinstatement sessions (r = .97, p < 0.001).