Metabotropic Glutamate 5 Receptor (mGluR5) Antagonists Decrease Nicotine Seeking, But Do Not Affect the Reinforcement Enhancing Effects of Nicotine

Abstract

Nicotine self-administration models typically evaluate the effects of smoking cessation aides on 'primary reinforcement' engendered by nicotine. However, the more recently described reinforcement enhancing effects of the drug are not always included in experimental analyses of potential therapeutics. We evaluated the effects of pretreatment with noncompetitive antagonists of the metabotropic glutamate 5 receptor (mGluR5) on each reinforcement-related effect of nicotine using a model in which a reinforcing visual stimulus (VS) and nicotine infusions were concurrently available. Five groups (2-lever, VS-only, NIC + VS, NIC-only, or SAL-only) were instrumented for self-administration. The 2-lever group could earn a nicotine infusion (0.06 mg/kg per infusion free base) for meeting the schedule on one lever (eg right), or VS for meeting the schedule on the other lever (eg left). The VS-only group could earn VS or saline under similar contingencies. Remaining rats could press one lever to earn both reinforcers (NIC + VS), nicotine infusions (NIC-only), or saline infusions (SAL-only); the other lever was 'inactive'. Responding on the VS lever in the 2-lever group was greater than that of the VS-only group, reflecting the reinforcement-enhancing effect of nicotine. Pretreatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) or 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) decreased nicotine intake as well as the enhanced responding for the concurrently available VS. In follow-up studies, replacing nicotine via experimenter-administered infusions sustained the drugs reinforcement enhancing effect; neither MPEP nor MTEP decreased the enhancing effects of nicotine. These findings are consistent with other studies suggesting that mGlu5 receptors mediate nicotine seeking, but do not alter the reinforcement enhancing effects of nicotine.

Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [ 11 C]ABP688 positron emission tomography

“…This study found that MPEP decreased the breakpoints for nicotine and cocaine in rats, implicating mGluR5 in the reinforcing properties of nicotine. In contrast, other studies have suggested that negative allosteric modulators of mGluR5 reduce nicotine seeking but do not interfere with the reinforcement enhancement, mood enhancement, and cognitive-function enhancement effects of nicotine (14,15). In a rat model of cocaine escalation, functional up-regulation of mGluR2/3 and downregulation of mGluR5 were found to be likely factors in the transition from cocaine use to cocaine dependence (16).…”

The Metabotropic Glutamate 2/3 Receptor Agonist LY379268 Blocked Nicotine-Induced Increases in Nucleus Accumbens Shell Dopamine only in the Presence of a Nicotine-Associated Context in Rats

“…Therefore, blockade of nicotine-induced dopamine release in the NAcc shell may not be the only mechanism by which LY379268 increases the latency to self-administer nicotine and attenuates nicotine intake. As described in the Introduction, LY379268 decreases glutamate release by activating inhibitory presynaptic mGlu2/3 receptors (Cartmell and Schoepp, 2000;Xi et al, 2002a), and blockade of glutamatergic neurotransmission also attenuates the reinforcing effects of nicotine (Kenny et al, 2009(Kenny et al, , 2003Palmatier et al, 2008;Paterson and Markou, 2005;Paterson et al, 2003). Therefore, mGlu2/3-mediated attenuation of glutamatergic neurotransmission is likely to be another mechanism contributing to LY379268-induced increases in the latency to self-administer nicotine (this study) and attenuation of the reinforcing effects of nicotine .…”

“…Nicotine increases glutamatergic transmission by activating excitatory nicotinic receptors located on presynaptic glutamatergic terminals (Fu et al, 2000;Mansvelder and McGehee, 2002;Reid et al, 2000). Blockade of glutamatergic neurotransmission by systemic administration of receptor antagonists that act at postsynaptically located ionotropic or metabotropic glutamate (mGlu) receptors attenuated both nicotine selfadministration (Kenny et al, 2009(Kenny et al, , 2003Palmatier et al, 2008;Paterson and Markou, 2005;Paterson et al, 2003) and nicotine-induced increases in NAcc dopamine release (Fu et al, 2000;Kosowski et al, 2004;Schilstrom et al, 1998;Sziraki et al, 2002).…”

Development of Novel Pharmacotherapeutics for Tobacco Dependence: Progress and Future Directions

“…These findings suggest that hypocretin-1 receptors may be viable targets for the development of smoking-cessation agents (Bartlett & Heilig, 2011;Kenny, 2011a;Plaza-Zabala, Maldonado, & Berrendero, 2012). Similar to hypocretin-1 receptors, metabotropic glutamate 5 (mGlu5) receptor antagonists have also been shown to reduce consumption of nicotine and other addictive in rats and mice (Bespalov et al, 2005;Chiamulera et al, 2001;Kenny et al, 2003;Palmatier, Liu, Donny, Caggiula, & Sved, 2008;Paterson & Markou, 2005;. Promisingly, the safety of the novel mGlu5 receptor antagonist AFQ056 was recently tested in a phase I clinical trial for smoking cessation.…”