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Perirhinal Cortex mGlu5 Receptor Activation Reduces Relapse to Methamphetamine Seeking by Restoring Novelty Salience
Jamie Peters1, Michael D Scofield1, Shannon M Ghee1
1Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
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-site-specific 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.
Insights
Long-term methamphetamine use impairs novelty recognition. Targeting perirhinal metabotropic glutamate 5 (mGlu5) receptors with DPFE restored this function and altered relapse behavior in rats, suggesting a potential therapeutic target for addiction.
Area of Science:
- Neuroscience
- Pharmacology
- Addiction Research
Background:
- Long-access methamphetamine self-administration in rats impairs novelty detection.
- This cognitive deficit is associated with downregulated metabotropic glutamate 5 (mGlu5) receptors in the perirhinal cortex.
- Novel positive allosteric modulators (PAMs) like DPFE offer improved properties for site-specific brain studies.
Purpose of the Study:
- To investigate the role of perirhinal mGlu5 receptors in methamphetamine-induced cognitive deficits.
- To assess the impact of a novel mGlu5 PAM, DPFE, on novel object recognition and relapse-related behaviors.
- To explore DPFE as a potential therapeutic target for methamphetamine use disorder.
Main Methods:
- Rats underwent long-access or short-access methamphetamine self-administration.
- Novel object recognition was tested.
- DPFE was infused into the perirhinal cortex.
- Methamphetamine-seeking behavior was assessed under standard and novel cue relapse conditions.
Main Results:
- DPFE infusion into the perirhinal cortex restored novel object recognition in long-access rats.
- Perirhinal DPFE did not affect meth-seeking in a standard cue relapse test.
- In a novel cue test, DPFE shifted responding in long-access rats, resembling short-access rats' behavior.
Conclusions:
- Perirhinal mGlu5 receptors are a viable target for restoring cognitive function in methamphetamine addiction.
- Targeting these receptors may help reduce relapse, especially when novel stimuli compete with conditioned cues.
- DPFE shows promise for treating cognitive impairments and potentially reducing relapse in addiction.
