ro-25-6981 and Amphetamine-Related-Disorders

Previous work suggests adolescent rats have deficient extinction consolidation relative to adults. Although the mechanisms underlying this age difference are currently unknown, studies in adult rats have implicated GluN2B-containing N-methyl-d-aspartate (NMDA) receptor function in extinction consolidation of drug-associated memory. Importantly, GluN2B neurotransmission emerges during adolescent development, and drugs of abuse during adolescence may delay the development of extinction consolidation by disrupting the ontogeny of GluN2B function. Here, we trained Sprague-Dawley rats of both sexes to self-administer methamphetamine [METH, 0.1 mg/kg/infusion intravenous (i.v.)] beginning during adolescence [postnatal (P) day 41] or adulthood (P91). Rats were given short access (2 h) to self-administer METH in seven daily sessions followed by 14 sessions with long access (6 h). Subsequently, rats underwent four daily 30-minute extinction sessions with immediate postsession injections of either a GluN2B antagonist [Ro25-6981; 6 mg/kg, intraperitoneal (i.p.)] or a vehicle solution. After four daily 2-h extinction sessions, a priming injection (1 mg/kg METH, i.p.) was given prior to a final 2-h reinstatement session. During LgA, adolescent-onset rats earn more METH than adult-onset rats and display greater drug-loading behavior. Rats reduced their drug-seeking behavior across the extinction sessions, with no significant group differences. Rats reinstated drug-seeking following the METH-priming injection, with females displaying greater reinstatement than males. These results do not support our a priori hypothesis that adolescent-onset METH use disrupts the ontogeny of GluN2B transmission and contributes to age-of-onset differences in extinction of METH-seeking. However, our findings suggest that age-of-onset contributes to excessive METH-taking, while sex confers vulnerability to relapse to METH-seeking.

Topics: Age Factors; Amphetamine-Related Disorders; Animals; Conditioning, Operant; Drug-Seeking Behavior; Extinction, Psychological; Female; Male; Memory; Memory Consolidation; Methamphetamine; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Self Administration; Sex Factors

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.

Topics: Amphetamine-Related Disorders; Animals; Central Nervous System Stimulants; Cycloserine; Excitatory Amino Acid Agents; Long-Term Synaptic Depression; Male; Memory Disorders; Methamphetamine; Phenols; Piperidines; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Self Administration; Tissue Culture Techniques