A dysphoric-like state during early withdrawal from extended access to methamphetamine self-administration in rats

Rationale: Negative emotional states during drug withdrawal may contribute to compulsive drug intake and seeking in humans. Studies suggest that extended access to methamphetamine induces compulsive drug intake in rats. Objective: The present study tested the hypothesis that compulsive methamphetamine intake in rats with extended access is associated with negative emotional states during drug withdrawal. Methods: Rats with short (1 h, ShA) and extended access (6 h, LgA) to methamphetamine self-administration (0.05 mg/kg/infusion) were tested for reward thresholds using intracranial self-stimulation (ICSS). Different groups of ShA and LgA rats were examined for depression-like and anxiety-like states in the novelty-suppressed feeding, open field, defensive burying, and forced swim tests. Results: With extended access, ICSS thresholds gradually increased, which was correlated with the increase of drug intake. During drug withdrawal, the increased ICSS thresholds returned to levels observed before exposure to extended access to methamphetamine. Upon re-exposure to extended access to methamphetamine, ICSS thresholds showed a more rapid escalation than during the initial exposure. LgA rats showed a longer latency to approach chow in the center of a novel field and remained immobile longer in the forced swim test than ShA rats did during early withdrawal. In contrast, ShA rats actively buried an aversive shock probe whereas LgA rats remained immobile in the defensive burying test. Conclusion: The data suggest that extended access to methamphetamine produces a more depressive-like state than anxiety-like state in rats during early withdrawal.