Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate N -methyl- d -aspartate receptor expression

Abstract

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.

Perirhinal Cortex mGlu5 Receptor Activation Reduces Relapse to Methamphetamine Seeking by Restoring Novelty Salience

“…Deficits in novel object recognition, or variants of the task, have been observed after repeated exposure to not only meth (Belcher et al, 2007;Gonzalez et al, 2014;O'Dell et al, 2010;Reichel et al, 2014;Reichel et al, 2012b;Rogers et al, 2008), but also cocaine (Briand et al, 2008), ecstasy (Schenk et al, 2010), and alcohol (Cippitelli et al, 2010;Zhao et al, 2012). A few of these studies implicated certain neural mechanisms within a circuit including the prefrontal cortex (Gonzalez et al, 2014;Kamei et al, 2005), hippocampus and entorhinal cortex (Zhao et al, 2012).…”

“…Self-administration was conducted in behavioral chambers (30 × 20 × 20 cm, Med Associates, St Albans, VT) as previously described (Reichel et al, 2014). Responding on the active lever delivered a 2-s infusion of meth (20 μg in 50 μl) followed by an unsignaled 20 s timeout period (FI-20 s) where responding was without consequence (to prevent overdose).…”

“…and cefazolin (200 mg/kg, s.c.) were administered preoperatively for analgesia and to protect against post-surgical infection, respectively. Intravenous catheters were surgically implanted as previously described (Reichel et al, 2014). For experiments requiring intracranial microinfusions, guide cannulas (Plastics One, Roanoke, VA) directed at the perirhinal cortex were stereotaxically implanted after the catheter surgery, under the same plane of anesthesia.…”

“…Total distance (cm) traveled was simultaneously recorded as a measure of ambulation during the test. Objects included a PVC pipe (6.4 × 3.8 cm), a light bulb (8.9 cm), and/or a plastic bottle (Reichel et al, 2014). Objects and the arena were wiped down with 70% ethanol between animals.…”

“…Long-access meth results in a number of neuroadaptations within the perirhinal cortex that may underlie this cognitive deficit, including a downregulation of glutamate receptors, specifically GluN2B-containing N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate 5 receptors (mGlu5; Reichel et al, 2014;Reichel et al, 2011;Scofield et al, 2015), both of which have been implicated in novel object recognition (Barker et al, 2006a;Barker et al, 2006b). Furthermore, restoring activity at perirhinal NMDA receptors using the partial agonist D-cycloserine restores novel object recognition in long-access meth rats (Scofield et al, 2015).…”