Chronic methamphetamine (meth) can lead to persisting cognitive deficits in human addicts and animal models of meth addiction. Here, we examined the impact of either contingent or noncontingent meth on memory performance using an object-in-place (OIP) task, which measures the ability to detect an object relative to its location and surrounding objects. Further, we quantified monoamine transporter levels and markers of neurotoxicity within the OIP circuitry and striatum. Male Long-Evans rats received an acute meth binge (4 × 4 mg/kg i.p., 2 hour intervals) or self-administered meth (0.02 mg/infusion, i.v.; 7 days for 1 hour/day, followed by 14 days for 6 hours/day). Rats were tested for OIP recognition memory following one week of withdrawal. Subsequently, transporters for serotonin (SERT) and norepinephrine (NET) were quantified using Western blot in tissue obtained from the hippocampus, perirhinal cortex, and prefrontal cortex. In addition, striatal dopamine transporters, tyrosine hydroxylase, and glial fibrillary acidic protein were measured to assess potential neurotoxicity. Control (saline-treated) rats spent more time interacting with the objects in the changed locations. In contrast, contingent or noncontingent meth resulted in disrupted OIP performance as seen by similar amounts of time spent with all objects, regardless of location. While only acute meth binge produced signs of neurotoxicity, both meth regimens decreased SERT in the perirhinal cortex and hippocampus. Only meth self-administration resulted in a selective decrease in NET. Meth-induced changes in SERT function in the OIP circuitry may underlie memory deficits independently of overt neurotoxic effects.

Background Chronic methamphetamine (meth) abuse in humans can lead to various cognitive deficits, including memory loss. We previously showed that chronic meth self-administration impairs memory for objects relative to their location and surrounding objects. Here, we demonstrate that the cognitive enhancer, modafinil, reversed this cognitive impairment independent of glutamate N-methyl d-aspartate (GluN) receptor expression. Methods Male, Long-Evans rats underwent a noncontingent (Experiment 1) or contingent (Experiment 2) meth regimen. After one week of abstinence, rats were tested for object-in-place recognition memory. Half the rats received either vehicle or modafinil (100 mg/kg) immediately after object familiarization. Rats (Experiment 2) were sacrificed immediately after the test and brain areas that comprise the key circuitry for object in place performance were manually dissected. Subsequently, glutamate receptor expression was measured from a crude membrane fraction using western blot procedures. Results Saline-treated rats spent more time interacting with the objects in changed locations, while meth-treated rats distributed their time equally among all objects. Meth-treated rats that received modafinil showed a reversal in the deficit, whereby they spent more time exploring the objects in the new locations. GluN2B receptor subtype was decreased in the perirhinal cortex, yet remained unaffected in the prefrontal cortex and hippocampus of meth rats. This meth-induced down regulation occurred whether or not meth experienced rats received vehicle or modafinil. Conclusions These data support the use of modafinil for memory impairment in meth addiction. Further studies are needed to elucidate the neural mechanisms of modafinil reversal of cognitive impairments.