Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia

Abstract

Rationale: Patients with schizophrenia exhibit high comorbidity for substance abuse, but the biological underpinnings of this dual-diagnosis condition are still unclear. Previous studies have shown that rats with a neonatal ventral hippocampal lesion (NVHL), a widely used developmental animal model of schizophrenia, exhibit increased cocaine and methamphetamine self-administration and cocaine-induced reinstatement.

Objective: Here, we assessed whether a NVHL would also potentiate cue-induced reinstatement of cocaine seeking and the time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving) in adult rats.

Methods: Rats were trained to self-administer cocaine (3 or 6 h/day with 0.75 mg kg(-1) infusion(-1) paired with a tone-light cue) for 10 days, followed by extinction training (3 h/day) and cue-induced reinstatement of cocaine seeking. Other rats were tested for incubation of cocaine craving, assessed in extinction tests 1 and 30 days after the last self-administration session.

Results: Although there was no significant difference in cocaine intake between NVHL and sham controls, NVHL rats took significantly longer to reach an a priori set extinction criterion and exhibited enhanced cue-induced reinstatement. However, while cue-induced cocaine seeking was higher after 30 days than after 1 day of withdrawal (incubation of cocaine craving), the NVHL had no effect on this incubation.

Conclusion: These data confirm previous reports on enhanced resistance to extinction after NVHL and demonstrate that NVHL rats exhibit enhanced cue-induced reinstatement of cocaine seeking after extinction, a measure of drug relapse.

Figure 1. Representative hippocampus from a control and NVHL rat

Photomicrographs from Nissl-stained brains from sham-treated (A) and NVHL (B) rats.

Figure 2. Enhanced cue-induced reinstatement of cocaine seeking after extinction in NVHL rats

(A) Histogram depicting number of infusions in 3-hour sessions in sham (filled squares) and NVHL (open circles) rats. (B) Plot of numbers of active and inactive lever presses during acquisition and the initial part of extinction training for sham and NVHL rats. (C) Histogram showing the rate at which rats in both groups achieve the extinction criterion. The data are illustrated as percent of rats that have not achieved the criterion in consecutive sessions. (D) Mean ± SEM number of presses on the active and inactive levers during extinction and reinstatement of cocaine seeking in NVHL and sham rats. **P<0.01 compared to sham, n=15–16 per group.

Figure 3. Time-dependent changes in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving) in NVHL and sham rats

(A) Number of infusions in both NVHL and sham rats during the cocaine self-administration phase. (B). Mean ± SEM number of presses on the active and inactive levers one day after the last self-administration session (Day 1) and 30 days after the last self-administration session (Day 30). ***P<0.001 compared to Day 1, n=7–8 per group.