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

Abstract

Rats that have self-administered methamphetamine (meth) under long access, but not short access, conditions do not recognize novel objects. The perirhinal cortex is critical for novelty detection, and perirhinal metabotropic glutamate 5 receptors (mGlu5) are downregulated after long-access meth. The novel positive allosteric modulator (PAM) 1-(4-(2,4-difluorophenyl) piperazin-1-yl)-2-((4-fluorobenzyl)oxy)-ethanone, or DPFE, demonstrates improved solubility compared with other mGlu5 PAMs, thus allowing brain-sitespecific pharmacological studies. Infusion of DPFE into perirhinal cortex restored novel object recognition in long-access meth rats. To investigate the impact of these cognitive enhancing effects on relapse, we tested the effects of DPFE infusions into perirhinal cortex on meth-seeking under two different test conditions. In the standard cue relapse test, perirhinal DPFE infusions did not alter meth-seeking in the presence of meth cues. However, in a novel cue relapse test, wherein animals were allowed to allocate responding between a novel cue and meth-conditioned cue, perirhinal DPFE infusions shifted the pattern of responding in long-access rats toward a profile resembling short-access rats, which respond equally for novel and meth cues. Perirhinal mGlu5 are thus a promising pharmacological target for the restoration of cognitive function in meth addicts. Targeting these receptors may also reduce relapse, particularly in situations where novel stimuli compete with conditioned stimuli for control over meth seeking.

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

“…DPFE, a structurally distinct ligand relative to the three previous classes, was also included to offer further insight into the relationship between chemical scaffold and pharmacological outcome. As with CDPPB & VU0409551 behavioral studies have been conducted with DPFE (Gregory et al, 2013a; Peters et al, 2015), thereby allowing the potential to link in vivo efficacies with in vitro pharmacological fingerprints.…”

AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving

“…Studies conducted after methamphetamine self-administration have similarly demonstrated both pro-cognitive effects of mGlu5 PAMs (57–59) and anti-relapse effects of mGlu5 NAMs (60). The latter effect was observed following limited-access methamphetamine self-administration and extinction training (60).…”

Methamphetamine self-administration modulates glutamate neurophysiology

“…In recent years, self-administration models that employ longer access to a drug also have received growing attention, likely owing to the noted differences between long- and short-access models (Ahmed and Koob 1998; Peters et al 2015; Reichel et al 2012). Long-access leads to a highly reproducible escalation of drug intake that is thought to reflect a more “addicted” state, versus short-access models that are thought to reflect “recreational” drug use (Ahmed and Koob 1998).…”