Loss of Object Recognition Memory Produced by Extended Access to Methamphetamine Self-Administration is Reversed by Positive Allosteric Modulation of Metabotropic Glutamate Receptor 5

Abstract

Chronic methamphetamine (meth) abuse can lead to persisting cognitive deficits. Here, we utilized a long-access meth self-administration (SA) protocol to assess recognition memory and metabotropic glutamate receptor (mGluR) expression, and the possible reversal of cognitive impairments with the mGluR5 allosteric modulator, CDPPB. Male, Long-Evans rats self-administered i.v. meth (0.02 mg/infusion) on an FR1 schedule of reinforcement or received yoked saline infusions. After 7 daily 1-h sessions, rats were switched to 6-h daily sessions for 14 days, and then underwent drug abstinence. Rats were tested for object recognition memory one week after meth SA at 90 min and 24 hour retention intervals. In a separate experiment, rats underwent the same protocol, but received either vehicle or CDPPB (30 mg/kg) after familiarization. Rats were sacrificed on day 8 or 14 post-SA and brain tissue was obtained. Meth intake escalated over the extended access period. Additionally, meth-experienced rats showed deficits in both short- and long-term recognition memory, demonstrated by a lack of novel object exploration. The deficit at 90 min was reversed by CDPPB treatment. On day 8, meth intake during SA negatively correlated with mGluR expression in the perirhinal and prefrontal cortex, and mGluR5 receptor expression was decreased 14 days after discontinuation of meth. This effect was specific to mGluR5 levels in the perirhinal cortex, as no differences were identified in the hippocampus or in mGluR2/3 receptors. These results from a clinically-relevant animal model of addiction suggest that mGluR5 receptor modulation may be a potential treatment of cognitive dysfunction in meth addiction.

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

“…While previous studies focused on mGlu 5 PAM reversal of psychostimulant-induced deficits in cognition (i.e., Reichel et al, 2011;Gastambide et al, 2013), we evaluated the ability of DPFE to facilitate the hippocampalmediated acquisition of contextual fear conditioning, a classic Pavlovian conditioning task (Phillips and LeDoux, 1992). Interestingly, DPFE enhanced acquisition of this cognitive task within a dose range significantly lower than that required to reverse amphetamine-induced hyperlocomotion, consistent with the previous report of lower doses of the mGlu 5 PAM ADX47273 needed to enhance performance in another cognition model (Liu et al, 2008b).…”

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

“…dose in SpragueÀDawley rats at 10 mg/kg as a 1 mg/mL 20% β-CD formulation gave sustained exposure with a plasma C max = 21 μM and moderate b/p = 0.13. Administration of 52 significantly reversed amphetamine-induced hyperlocomotion at doses of 30, 56.6, and 100 mg/kg after i.p. administration and at doses of 56.6 and 100 mg/kg orally using the aqueous vehicle 20% β-CD.…”

“…Another interesting aspect of mGlu 5 activation recently uncovered using CDPPB is the ability of potentiation of mGlu 5 to facilitate extinction of memories associated with drug-addiction and drugseeking behavior 54,55 as well as reversal of deficits in novel object recognition due to methamphetamine access. 56 More recently, the Merck team reported on the effect of CDPPB in novel object recognition and was able to examine across similar doses the effects of CDPPB on several protein markers of synaptic plasticity in prefrontal cortex and hippocampus ex vivo. 57 Interestingly, behavior outcomes and several protein markers in the prefrontal cortex were characterized by an inverted U-shaped doseÀeffect relationship, suggesting that, at least for CDPPB or CDPPB-like compounds, dose selection for potential compounds entering clinical trials with cognition enhancing end points could prove challenging.…”

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

“…Systemic administration of the mGlu5-positive allosteric modulator (PAM) 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide, or CDPPB, similarly restores novel object recognition in long-access meth rats (Reichel et al, 2011). With the recent advent of a more soluble, selective mGlu5 PAM, 1-(4-(2,4-difluorophenyl) piperazin-1-yl)-2-((4-fluorobenzyl)oxy)-ethanone, or DPFE (Gregory et al, 2013), a potential perirhinal locus for this effect can now be investigated using brain-site specific microinfusions.…”

“…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).…”