Effects of the Positive Allosteric Modulator of Metabotropic Glutamate Receptor 5, VU-29, on Maintenance Association between Environmental Cues and Rewarding Properties of Ethanol in Rats

Abstract

Metabotropic glutamate subtype 5 (mGlu5) receptors are implicated in various forms of synaptic plasticity, including drugs of abuse. In drug-addicted individuals, associative memories can drive relapse to drug use. The present study investigated the potential of the mGlu5 receptor positive allosteric modulator (PAM), VU-29 (30 mg/kg, i.p.), to inhibit the maintenance of a learned association between ethanol and environmental context by using conditioned place preference (CPP) in rats. The ethanol-CPP was established by the administration of ethanol (1.0 g/kg, i.p. ×10 days) using an unbiased procedure. Following ethanol conditioning, VU-29 was administered at various post-conditioning times (ethanol free state at the home cage) to ascertain if there was a temporal window during which VU-29 would be effective. Our experiments indicated that VU-29 did not affect the expression of ethanol-induced CPP when it was given over two post-conditioning days. However, the expression of ethanol-CPP was inhibited by 10-day home cage administration of VU-29, but not by first 2-day or last 2-day injection of VU-29 during the 10-day period. These findings reveal that VU-29 can inhibit the maintenance of ethanol-induced CPP, and that treatment duration contributes to this effect of VU-29. Furthermore, VU-29 effect was reversed by pretreatment with either MTEP (the mGlu5 receptor antagonist), or MK-801 (the N-methyl-D-aspartate-NMDA receptor antagonist). Thus, the inhibitory effect of VU-29 is dependent on the functional interaction between mGlu5 and NMDA receptors. Because a reduction in ethanol-associated cues can reduce relapse, mGlu5 receptor PAM would be useful for therapy of alcoholism. Future research is required to confirm the current findings.

Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders

“…mGluR5 plays an important role in both LTP and LTD, suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. VU-29, a mGlu5 receptor PAM, in previous study, ameliorated many ethanol effects, including memory deficits induced by ethanol [53,103]. In the present experiments, this compound reversed recognition memory deficits induced by MS alone, as well as those induced by MS and potentiated by ethanol.…”

Memantine Prevents the WIN 55,212-2 Evoked Cross-Priming of Ethanol-Induced Conditioned Place Preference (CPP)

“…at a dose of 1.0 g/kg. This ethanol dosage regimen was established in our previous study, wherein the dose of 1.0 g/kg conditioned place preference in rats [ 74 ]. Memantine hydrochloride (Tocris Bioscience, Bristol, UK) was dissolved in saline and administered i.p.…”

“…The CPP procedure was based on methods described previously [ 74 , 75 ], with minor modification. The CPP procedure (unbiased design) consisted of six different phases: habituation (1 day), pre-test (1 day), conditioning (10 days), test (1 day), extinction (7 days) and reinstatement (1 day) as described below.…”