Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

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Abstract
Rationale Methamphetamine is a highly addictive psychostimulant, and chronic methamphetamine users show high rates of relapse. Furthermore, prolonged methamphetamine abuse can lead to psychiatric symptoms and has been associated with various cognitive dysfunctions. However, the impact of self-administered methamphetamine on cognitive dysfunction and relapse has not been concurrently examined in an animal model. Objectives The present study determined the effects of short- vs. long-access contingent methamphetamine on self-administration, extinction responding, reinstatement of methamphetamine seeking, and cognitive performance on an object exploration task. Materials and methods Long-Evans rats self-administered methamphetamine i.v. (0.02 mg/infusion) or received saline during daily sessions (1 or 2 h) for 10 days, followed by either maintained short- (1 or 2 h) or long-access (6 h) self-administration for 14 days. Lever responding was extinguished prior to reinstatement, which consisted of presentation of drug-paired cues or a priming injection of methamphetamine (1.0 mg/kg). Animals were also tested on an object exploration task prior to self-administration and at 10–12 days after cessation of self-administration, thus providing a comparison of pre-methamphetamine exposure with post-methamphetamine exposure. Results Long-access methamphetamine self-administration resulted in escalation of daily intake. Furthermore, animals in both short- and long-access groups showed robust conditioned-cued and drug-primed reinstatement, with long access resulting in enhanced methamphetamine-primed reinstatement. Methamphetamine self-administration also led to access-dependent impairments on novel object recognition but failed to impair recognition of spatial reconfiguration. Conclusions Extended methamphetamine self-administration enhances drug-primed reinstatement and decreases novel object recognition, indicating that prolonged contingent methamphetamine increases motivation for drug seeking following withdrawal while increasing cognitive deficits.

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