Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking

Abstract

Accumulating evidence suggests that metabotropic glutamate receptors (mGluRs) are involved in both cocaine reinforcement and the reinstatement of cocaine-seeking behavior. In the present experiments, rats were trained to self-administer cocaine under fixed ratio (for cocaine priming-induced reinstatement) or second-order (for cocaine cue-induced reinstatement) schedules of reinforcement. Lever pressing was then extinguished followed by a reinstatement phase where operant responding was promoted by either cocaine itself or cocaine-associated light cues. Results indicated that systemic administration of the mGluR5 antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP: 1 and 3mg/kg i.p.) or 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP: 0.1 and 1mg/kg i.p.) dose-dependently attenuated reinstatement of drug seeking induced by a systemic priming injection of 10mg/kg cocaine. Systemic administration of MTEP (0.1 and 1mg/kg i.p.) also dose-dependently attenuated cocaine cue-induced reinstatement of drug seeking. Systemic administration of neither MPEP nor MTEP influenced the reinstatement of sucrose seeking, which indicates that the effects of these compounds on cocaine seeking were reinforcer specific. Additionally, administration of MPEP (1microg/0.5microl) into the nucleus accumbens shell, a brain region that plays a critical role in cocaine seeking, attenuated cocaine priming-induced reinstatement of drug seeking. These results add to a growing literature indicating that mGluR antagonists attenuate the reinstatement of cocaine seeking. Importantly, the current findings also suggest that activation of mGluR5s specifically in the nucleus accumbens shell may promote the reinstatement of cocaine seeking.

Figure 1

The mGluR5 selective antagonist MTEP attenuates reinstatement of cocaine seeking. A) Mean number of active lever responses on last day of cocaine self-administration, extinction and during the reinstatement of drug seeking by a cocaine priming injection (10 mg/kg, i.p.). B) Responses on active and inactive levers following the administration of vehicle (1% DMSO) or varying concentrations of MTEP. MTEP dose-dependently attenuated cocaine priming-induced reinstatement of cocaine seeking. The asterisks represent significant differences from vehicle (p< 0.05, Tukey’s HSD). Inset: Systemic MTEP had no influence on the reinstatement of sucrose seeking. C) Average of active lever responses on last day of cocaine self-administration using a second-order schedule of reinforcement [FI5(FR5)]. Mean of active lever responses on the last day of extinction and during cue-induced reinstatement of cocaine seeking also are depicted. D) MTEP dose-dependently attenuated cue-induced reinstatement of cocaine seeking. The asterisk represents a significant difference from vehicle pretreatment (p<0.05, Tukey’s HSD). All data are expressed as mean (± SEM) active or inactive lever pressing per session.

Figure 2

Systemic and intra-accumbens shell administration of MPEP, a non-competitive negative modulator of mGluR5 receptors, attenuates cocaine priming-induced reinstatement of cocaine seeking. A) Systemic MPEP dose-dependently blocks priming-induced reinstatement of cocaine seeking. MPEP also attenuated inactive lever responses at the highest dose tested (3 mg/kg). However, the lowest effective dose of MPEP (1.0 mg/kg) had no effect on inactive lever responses. B) Time course of active lever responses in the vehicle (1% DMSO) + cocaine and 1.0 mg/kg MPEP + cocaine treatments. C) The lowest dose of MPEP (1.0 mg/kg) effective in blocking reinstatement of cocaine seeking did not affect reinstatement of sucrose seeking. D) Intra-accumbens shell microinjection of MPEP dose-dependently attenuated cocaine priming-induced reinstatement of drug seeking. E) Time course of active lever responses in the vehicle (1% DMSO) + cocaine and 1.0 μg MPEP + cocaine treatments. F) Coronal sections of the brain at the level of the nucleus accumbens depicting locations cannulae within the shell of the accumbens. All data are expressed as mean (± SEM). Asterisks represent significant differences from vehicle pretreatment (p<0.05, Tukey’s HSD).