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 priminginduced 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 3 mg/kg i.p.) or 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP: 0.1 and 1 mg/kg i.p.) dose-dependently attenuated reinstatement of drug seeking induced by a systemic priming injection of 10 mg/kg cocaine. Systemic administration of MTEP (0.1 and 1 mg/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 (1 μg/0.5μl) 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 promotes the reinstatement of cocaine seeking.

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…In addition, reductions in the intracellular scaffolding protein, Homer1b/c, which is known to functionally link mGluR5 with ionotropic glutamate receptors Tu et al, 1999;Naisbitt et al, 1999;Tu et al, 1999) is also reduced in the core (Swanson et al, 2001), suggesting a possible reduction in mGluR5 signaling efficacy. In contrast, in the NAc shell, mGluR5 antagonism reduces cocaineand cue-induced reinstatement of drug-seeking behavior (Kumaresan et al, 2009) and cocaine-induced reductions in AMPAR signaling (present study), indicating that to some degree mGluR5-mediated signaling in this region remains intact. Interestingly, in the NAc shell, MTEP application to slices from saline-treated mice increased mEPSC amplitude, suggesting that mGluR5 activity under basal (saline) conditions may normally serve to temper synaptic potentiation (Robbe et al, 2002).…”

Cocaine Decreases Metabotropic Glutamate Receptor mGluR1 Currents in Dopamine Neurons by Activating mGluR5

“…In addition, in medium spiny neurons, negative allosteric modulation of mGluR1s leads to an increase of cocaineinduced cellular plasticity (Bellone and Luscher, 2006;Loweth et al, 2013). In multiple behavioral studies, negative modulation of mGluR5 decreased the behavioral effects of cocaine, decreasing cocaine self-administration, cocaine seeking, and cue-induced reinstatement (Keck et al, 2013(Keck et al, , 2014Kumaresan et al, 2009;Platt et al, 2008). This study provides a link between these behavioral studies and cellular studies by showing that negatively modulating mGluR5 in vivo can prevent a cocaine-induced decrease in mGluR1 signaling.…”

“…Inhibition of mGluR5 by a variety of selective negative allosteric modulators or genetic knockout decreased cocaine self-administration (Kenny et al, 2005;Chiamulera, 2001), cue-induced reinstatement (Kumaresan et al, 2009), cocaine taking and seeking (Keck et al, 2013(Keck et al, , 2014, and extinction in rats and monkeys (Bird et al, 2014;Keck et al, 2013Keck et al, , 2014Kumaresan et al, 2009;Platt et al, 2008). Thus, blocking mGluR5 activity decreased behaviors associated with cocaine treatment and self-administration, whereas blockade of mGluR1 facilitated cocaine-dependent processes on AMPA receptor-dependent EPSCs in the nucleus accumbens (Loweth et al, 2013).…”

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

“…However, the dose of the antagonist (10mg/kg IP) required to elicit a significant reduction of cueinduced responding for nicotine is relatively high when compared with the dose of MPEP (1mg/kg) required to decrease cue-induced reinstatement of responding for cocaine (Kumaresan et al 2009 …”