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.

Keywords: VU-29; conditioned place preference; ethanol; mGlu5 receptor; memory; positive allosteric modulator; reward.

Figure 1

Experimental design for the effect of VU-29 on short-time maintenance of ethanol-induced CPP (A). Data are shown as post-conditioning minus pre-conditioning time (s) spent in the drug-associated compartment in the CPP Test 2 (B). Dots represent individual measurements, the central horizontal mark is the mean, and error bars represent SEM. *** p < 0.001 vs. vehicle.

Figure 2

Experimental design for the effect of VU-29 administered in three different combinations on long-time maintenance of ethanol-induced CPP (A). Data are shown as post-conditioning minus pre-conditioning time (s) spent in the drug-associated compartment in the CPP Test 2 (B). Dots represent individual measurements, the central horizontal mark is the mean, and error bars represent SEM. *** p < 0.001 vs. vehicle; ^^^ p < 0.001 vs. ethanol-treated group.

Figure 3

Experimental design for the influence of MK-801 and MTEP on the effect of VU-29 on the maintenance of ethanol-induced CPP (A). Data are shown as post-conditioning minus pre-conditioning time (s) spent in the drug-associated compartment in the CPP Test 2 (B). The influence of MK-801 and MTEP on CPP score in vehicle-treated rats in the CPP Test 2 (C). Dots represent individual measurements, the central horizontal mark is the mean, and error bars represent SEM. *** p < 0.001 vs. vehicle; ^### p < 0.001 vs. ethanol-treated group; ^&& p < 0.01, ^&&& p < 0.001 vs. 10 Day VU-29-treatment.

Figure 4

Experimental design for the effect of VU-29 on rat behavior in the CPP procedure (A). Data are shown as post-conditioning minus pre-conditioning time (s) spent in the drug-associated compartment in the CPP Test (B). Dots represent individual measurements, the central horizontal mark is the mean, and error bars represent SEM.