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

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.

Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion

“…In support of this, an escalation of Meth intake was observed in rats switched to long access (6 h/day) but not in rats maintained on limited access (1 h/day), which is in agreement with previous studies (Kitamura et al, 2006;Rogers et al, 2008). As a result, we observed robust Meth self-administration (70 -110 mg/kg over the 2 weeks) in the long-access rats.…”

“…It is significant that chronic Meth use in humans is typically associated with high rates of relapse. As reported previously (Rogers et al, 2008), long-access Meth animals displayed a significant enhancement of Meth-primed reinstatement, a finding similar to that seen after chronic cocaine self-administration (Mantsch et al, 2004;Kippin et al, 2006). In the current study, reinstatement tests with a range of priming doses (0.3-3.0 mg/kg) were performed after 10 days of extinction to assess potential long-term changes in sensitivity to drug effects.…”

“…As opposed to Meth-primed reinstatement in which differences between short-and long-access animals were evident, there was no difference in cue reactivity between groups. The lack of difference in cue reactivity has been reported previously (Rogers et al, 2008) and may reflect the extensive overtraining with the cues that all animals experienced, regardless of daily access duration. Additional forms of conditioned cued reinstatement (e.g., contextual cues) or changes in cue parameters are warranted in future studies to reveal possible access-dependent differences in relapse.…”

“…Meth self-administration in rodents constitutes an addiction model with greater face validity than noncontingent drug administration models. Similar to human Meth abusers, rats with extended access to intravenous Meth demonstrate escalation of drug intake (Kitamura et al, 2006), enhanced drug seeking and increased cognitive deficits (Dalley et al, 2007;Rogers et al, 2008) relative to animals trained in shorter Meth access protocols that do not elicit escalated drug intake. In contrast to drugs such as cocaine, there is little information available on the neurobiological consequences of chronic Meth self-administration.…”

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

“…This procedure, like other paradigms that incorporate a period of long access 19,30,31 reasonably simulates some aspects of substance use disorders; it demonstrates both escalation of use and high motivation to obtain drug with early session "drug-loading," which are important aspects of human dependence versus recreational use 19,30 . Rodents who have long access exposure to IV methamphetamine also demonstrate cognitive deficits 32 , distinct responses to pharmacological treatment 33 , pharmacokinetics 34 and neurochemical changes 35 that are more similar to humans suffering from chronic methamphetamine use disorder than rodents with only short access exposure.…”