mGluR5 is necessary for maintenance of methamphetamine-induced associative learning

Abstract

Conditioned place preference (CPP) reflects the significance of contextual cues that are associated with rewarding effects of abused drugs such as methamphetamine (Meth). Glutamate neurotransmission is augmented following exposure to stimulants and associated cues. Activation of group I metabotropic glutamate receptors (mGluR) is critical for the acquisition and expression of stimulant-induced CPP. We hypothesized that the maintenance of Meth-induced CPP would also require activated mGluR, and that the role of mGluR1 vs. mGluR5 group I subtypes may differ. To test this hypothesis, negative allosteric modulators (NAMs) of these receptors were administered following the development of Meth-induced CPP. NAMs exert their functional effects by displacing agonist from agonist-occupied receptors, thus NAMs selectively target brain regions with glutamate release. Conditioning with Meth every other day for six days resulted in significant preference for the Meth-paired compartment. Two once-daily injections of the mGluR1 NAM, JNJ16259685 (0.3mg/kg, i.p.) or its vehicle on days 13 and 14 after Meth-conditioning did not influence the maintenance of Meth-induced CPP; however, administration of the mGluR5 NAMs MTEP (3mg/kg, i.p.) and MPEP (30 mg/kg, i.p.) inhibited maintenance processes necessary for CPP to be expressed. These findings suggest a subtype-specific role of mGluR5 receptors in the maintenance of place preference memory and potential of mGluR5 NAMs as a useful target for Meth addiction therapy.

Figure 1. The mGluR5 NAMs MTEP and MPEP, but not the mGluR1 NAM JNJ1625985, inhibit the expression of Meth-CPP

A) Timeline of treatment and testing. Ø, no treatment; M, methamphetamine (1mg/kg, i.p.); S, saline (1ml/kg, i.p.); V, vehicle (1ml/kg, i.p.). B) Rats treated with vehicle (n=11), C) JNJ16259685 at 0.3mg/kg (n=12), or D) JNJ16259685 at 3mg/kg (n=12) demonstrated a significant difference in amount of time spent in the Meth- vs. saline-paired chamber during CPP Test 1 and 2. D) Rats treated with the mGluR5 NAM MTEP (n=15) demonstrated a significant preference for the Meth-paired chamber during CPP Test 1, but the preference was not observed during CPP Test 2. E) Rats treated with MPEP (n=9) did not maintain the significant preference for the Meth-paired chamber after days 17 and 18 intervening NAM treatments. Data represent mean ± SEM. Repeated measure ANOVA with post-hoc Newman Keuls test for multiple comparisons, **p<0.01