Abstract
Exposure to methamphetamine (meth) can produce lasting memory impairments in humans and rodents. We recently demonstrated that extended access meth self-administration results in novel object recognition (NOR) memory deficits in rats. Recognition of novelty depends upon intact perirhinal (pRh) cortex function, which is compromised by meth-induced downregulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors. NMDA receptors containing this subunit have a critical role in pRh long-term depression (LTD), one of the primary physiological processes thought to underlie object recognition memory. We hypothesized that meth-induced downregulation of GluN2B receptors would compromise pRh LTD, leading to loss of NOR memory. We found that meth self-administration resulted in an inability to induce pRh LTD following 1 Hz stimulation, an effect that was reversed with bath application of the NMDA receptor partial agonist D-cycloserine (DCS). In addition, pRh microinfusion of DCS restored meth-induced memory deficits. Furthermore, blockade of GluN2B-containing NMDA receptors with Ro 25-6981 prevented DCS restoration of pRh LTD in meth subjects. Thus, targeting pRh LTD may be a promising strategy to treat meth-induced cognitive impairment.