Failure to Recognize Novelty after Extended Methamphetamine Self-Administration Results from Loss of Long-Term Depression in the Perirhinal Cortex

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 40; no. 11; pp. 2526 - 2535
• Main Authors: Scofield, Michael D, Trantham-Davidson, Heather, Schwendt, Marek, Leong, Kah-Chung, Peters, Jamie, See, Ronald E, Reichel, Carmela M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2015
• Subjects: Abstinence; Addictions; Amphetamine-Related Disorders - drug therapy; Amphetamine-Related Disorders - physiopathology; Animals; Central Nervous System Stimulants - administration & dosage; Cognitive ability; Cycloserine - pharmacology; Excitatory Amino Acid Agents - pharmacology; Laboratory animals; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - physiology; Male; Memory; Memory Disorders - chemically induced; Memory Disorders - physiopathology; Methamphetamine; Methamphetamine - administration & dosage; Neurosciences; Original; Phenols - pharmacology; Physiology; Piperidines - pharmacology; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Recognition (Psychology) - drug effects; Recognition (Psychology) - physiology; Self Administration; Tissue Culture Techniques; United States > US
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2015.99

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.