Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Abstract

Stimulatory actions of nicotine on mesocorticolimbic dopamine transmission are partly mediated by nicotine-induced glutamate release acting on ionotropic and metabotropic glutamate (mGlu) receptors. Because both presynaptic inhibitory mGlu2/3 and postsynaptic excitatory mGlu5 receptors provide potential targets for treatment of aspects of nicotine dependence, we examined interacting effects of mGlu5 (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and mGlu2/3 (LY341495) receptor antagonists on nicotine self-administration and brain reward threshold elevations associated with spontaneous nicotine withdrawal in rats. We hypothesized that increasing glutamate transmission by blocking presynaptic inhibitory mGlu2/3 autoreceptors would antagonize MPEP-induced decreases in nicotine self-administration. We also hypothesized that blocking postsynaptic actions of glutamate on mGlu5 receptors would exacerbate nicotine withdrawal-induced reward deficits, and that this effect would be attenuated by co-administration of the mGlu2/3 receptor antagonist LY341495. MPEP selectively decreased nicotine, but not food, self-administration in rats. LY341495 slightly decreased both nicotine and food self-administration. Co-administration of LY341495 with MPEP attenuated the effectiveness of MPEP in decreasing nicotine intake, although MPEP was still effective. Spontaneous nicotine withdrawal induced somatic signs of withdrawal and reward threshold elevations indicating reward deficits. MPEP increased somatic signs and reward deficits in both nicotine-and saline-withdrawing rats. Thus, while mGlu5 receptor antagonists may be therapeutically useful in decreasing tobacco smoking, they worsen nicotine withdrawal. Coadministration of LY341495 reduced MPEP-induced reward deficits in both nicotine-and salinewithdrawing rats. Thus, increasing glutamate transmission via mGlu2/3 autoreceptor blockade reduces the effects of mGlu5 receptor blockade on nicotine self-administration and MPEP-induced exacerbation of brain reward deficits associated with nicotine withdrawal.

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

“…Although these findings seem to be complementary, we have previously argued that parallels between ICSS and sensory reinforcement should be made judiciously (Palmatier et al, 2007b). For example, the present findings that blockade of mGlu5 receptors did not affect responding for sensory reinforcement per se, may contrast with recent findings from the ICSS paradigm showing that MPEP decreased brain reward function (eg Liechti and Markou, 2007). Arguably, a change in brain reward function induced by the mGluR5 antagonists should have been accompanied by a decrease, or possibly a compensatory increase, in responding for sensory reinforcement (VS-only group).…”

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

“…Thus, the effects of the local administration of MPEP into the accumbal shell closely resemble the effects of systemic administration of the drug on responding for a nicotine or food reward (Paterson et al 2003;Paterson and Markou 2005;Liechti and Markou 2007a). Bilateral microinjection of MPEP at a dose of 20 µg per side depressed responding for both nicotine and food whereas doses above or below this had no significant effects on responding for either reinforcer.…”

“…The administration of mGluR5 antagonists to animals trained to respond for nicotine in an intravenous self-administration paradigm has consistently been shown to result in a dose-dependent attenuation of nicotine-seeking behaviour (Kenny et al 2003;Paterson et al 2003;Tessari et al 2004;Liechti and Markou 2007a;Palmatier et al 2007;Tronci et al 2010). Moreover, pretreatment with the mGluR5 antagonist, MPEP, is reported to decrease the break point for nicotine in a progressive ratio schedule of reinforcement (Paterson and Markou 2005).…”

“…The authors suggested that the paradigm modelled the anhedonia experienced by many smokers when they quit smoking. Liechti and Markou (2007a) explored the effects of the mGluR5 antagonist, MPEP, on both measures of withdrawal and found that it increased both measures.…”

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…The EVH1 domain exhibits a high degree of similarity across Homer isoforms and is essential for Homer interactions with a proline-rich sequence (PPSPF) displayed by proteins regulating drug-induced alterations in neuronal morphology, synaptic architecture, and glutamate receptor signaling/intracellular calcium dynamics. Of particular relevance to drug-induced neuroplasticity [e.g., 20,73,74,[78][79][80][81][82][89][90][91][92][93][94][95][96][97][98][99][100][123][124][125][126][127][128][129][130], these proteins include the mGluR1a and mGluR5 subtypes of Group 1 metabotropic glutamate receptors (mGluRs) [34,102,104,107,[131][132][133][134][135][136][137], the NMDA glutamate receptor scaffolding protein Shank [38,132,138,139], the inositol-1,4,5-triphosphate (IP3) receptor, a down-stream mediator of Group1 mGluR signaling [133,[140]…”