GluR2-3Y Inhibits the Acquisition and Reinstatement of Morphine-Induced Conditioned Place Preference in Rats

Abstract

Accumulating evidence indicates that a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) are involved in the relapse to abused drugs. However, the role of AMPARs containing the GluR2 subunit in opiate addiction is still unclear. GluR2-3Y, an interfering peptide, prevents the endocytosis of AMPARs containing the GluR2 subunit. In this study, we explored the effect of intravenous injection of GluR2-3Y on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (mCPP) in rats. We found that infusion of GluR2-3Y (1.5 nmol/g) one hour before morphine during the conditioning phase inhibited the acquisition of mCPP, while an identical injection one hour before the post-conditioning test had no influence on the expression of mCPP. Injection of GluR2-3Y (1.5 nmol/g) after mCPP extinction blocked the morphine-induced reinstatement of mCPP. Our results strongly support the hypothesis that inhibition of AMPAR endocytosis provides a new target for the treatment of opiate addiction.

Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction

“…AMPARs are expressed at the cell surface in a dynamic equilibrium between receptor insertion into the membrane versus receptor endocytosis, both of which are critical for drug memory formation and recall (Lüscher and Malenka 2011). In line with this, interfering with the endocytosis of GluA2-containing AMPAR using a blocking peptide prevents the acquisition, but not the expression of opioid CPP (Lin et al 2016; but see Dias et al 2012), and this effect is localized to the nucleus accumbens shell (NAshell) (Graziane et al 2016).…”

“…Ionotropic glutamate receptor signaling is necessary for extinction and reinstatement of opioid seeking in rodents, and is implicated in opioid addiction in humans, where polymorphisms in the AMPAR regulatory protein gene CNIH3 are linked to opioid dependence (Nelson et al 2016). Systemic AMPAR antagonist treatment, or blockade of GluA2-AMPAR endocytosis, facilitates extinction and blocks the reinstatement of morphine CPP (Dias et al 2012;Lin et al 2016;Siahposht-Khachaki et al 2017). However, AMPAR endocytosis may differentially affect the reinstatement of opioid CPP depending on the brain region targeted and the time point of intervention.…”

Ca2+‐permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease

“…Likewise, various molecular approaches, including the use of small interfering peptides (Fosgerau & Hoffmann, 2015), have been used successfully to target protein-protein interactions and prevent the endocytosis of AMPARs involved in behavioural sensitization models of drug addiction (Dias et al 2012). Small interfering peptides have also been developed to selectively prevent endocytosis of AMPARs containing GluA2 subunits (Lin et al 2016). Clearly, it would be of interest to further develop such approaches to target specific auxiliary subunits that may be involved in CP-AMPAR delivery.…”

“…Small interfering peptides have also been developed to selectively prevent endocytosis of AMPARs containing GluA2 subunits (Lin et al . 2016). Clearly, it would be of interest to further develop such approaches to target specific auxiliary subunits that may be involved in CP‐AMPAR delivery.…”

Drug addiction: a curable mental disorder?

“…Pharmacological modulations of AMPARs and NMDARs could attenuate abuse-related behaviors of drugs. The interested readers are referred to other excellent reviews for more information on this topic [29][30][31][32]. It should be noted that although many compounds that antagonize ionotropic glutamate receptors show efficacy to prevent addictive-like behaviors, most of them are not suitable for clinical use because of their potential side effects.…”