Metabotropic glutamate receptor 5 within nucleus accumbens shell modulates environment-elicited cocaine conditioning expression

Abstract

The metabotropic glutamate receptors 5 (mGluRs5) within the Nucleus Accumbens (NAc) have been implicated in the modulation of psychostimulant reward. We hypothesized that blockade of mGluR5 within the NAc shell would impair cocaine conditioning in rats. For this study, animals were implanted with cannulae within the NAc shell, and separate groups were exposed to a multimodal environment within activity chambers that signaled cocaine (cocaine-paired) or saline (controls, cocaine-unpaired) injections. Prior to placing the animals in the chambers, rats received systemic intraperitoneal injections of saline or cocaine for 10 consecutive sessions. In the test session (D12), animals were exposed to the multimodal environment without any cocaine or saline pre-treatment. Before placing the rats in the chambers, separate groups of animals were infused within the NAc shell with 2.5, 12 or 25nmol/0.5μl/side of 2-methyl-6- (phenylethynyl) pyridine (MPEP), an antagonist of mGluR5 or with vehicle. Blockade of the mGluR5 subtype at a 2.5nmol dose showed no significant difference in either the ambulatory distance (AD) or the vertical plane move time (VPT). In contrast, mGluR5 blockade at 12nmol and 25nmol decreased conditioned locomotion in the cocaine-paired groups. An association of the environmental cues with the effects of cocaine implies the involvement of memory process during the conditioning response. Our results suggest that mGluR5 within the NAc shell could be modulating the expression of memory related to the association of environmental cues with the effects of cocaine. We suggest that mGluR5 could be taking into account to further studies related with cocaine exposure and cocaine addiction treatments.

mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism

“…In the present study, we found that systemic or local administration of MPEP into the NAc significantly inhibits cocaine self-administration under FR2 and/or PR reinforcement schedules, oral sucrose self-administration under PR reinforcement, as well as cocaine-induced reinstatement of drug-seeking behaviors. This is consistent with previous reports that pretreatment with MPEP or other mGluR5 antagonists (MTEP, fenobam, MFZ 10-7) inhibit cocaine self-administration 1 , 3 , 4 , 6 – 9 or cocaine-induced reinstatement of drug-seeking behavior 7 – 11 , 34 , 35 . Surprisingly, MPEP, at the same or higher doses, neither altered oral sucrose self-administration under FR2 reinforcement nor reinstatement of cocaine-seeking behavior triggered by cocaine-associated cues or footshock stress.…”

The mGlu5 receptor regulates extinction of cocaine-driven behaviours

“…In line with an interpretation of an extinction deficit is the exaggerated conditioned hyperactivity when mGlu5-deficient mice are returned (drug-free) to an environment previously paired with cocaine (Bird et al, 2010), suggesting a possible role for mGlu5 signalling in the integration of contextual information related to drug action. In agreement with this hypothesis, a recent study showed that intra-accumbal (shell) injection of MPEP acutely prior to a test session reduced conditioned hyperactivity (Martinez-Rivera et al, 2013), again implying a role for mGlu5 signalling in the learning process for association of environment/context and drug action.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Importantly, infusion of MTEP into the NAcore had no effect on cue-induced sucrose seeking (Sinclair et al, 2012), making blockade of postsynaptic mGluR5 a more attractive pharmacological approach for preventing drug seeking than the activation of presynaptic mGluR2/3 receptors (Olive, 2009). Infusion of the mGluR5 antagonist MPEP, directly into the NAshell, also reduces cocaine contextinduced locomotion (Martínez-Rivera et al, 2013) as well as cocaine-primed reinstatement of cocaine seeking (Kumaresan et al, 2009). However, it is important to note that although MPEP and MTEP are both mGluR5 antagonists, studies show that MPEP may inhibit NMDARs to a certain extent, whereas MTEP has fewer off-target effects and is more selective for mGluR5 than mGluR1 compared with MPEP (Lea and Faden, 2006).…”