A Role for mGluR5 Receptors in Intravenous Methamphetamine Self‐Administration

Abstract

Selective antagonists of the mGluR5 receptor attenuate rewarding and reinforcing effects of various drugs of abuse, including alcohol, nicotine, and cocaine. However, the ability of mGluR5 antagonists to alter the reinforcing effects of methamphetamine has not yet been explored. In this study, male Sprague-Dawley rats were trained to perform an operant lever-pressing task in order to obtain intravenous infusions of methamphetamine (0.2 mg/kg/infusion) or presentation of food pellets on a fixed ratio (FR1) schedule of reinforcement. After stabilization of methamphetamine or food self-administration, the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]pyridine (MTEP; 0.3, 1.0, or 3.0 mg/kg i.p.) or vehicle were administered to the animals in a randomized counterbalanced cross-over design. MTEP at doses of 1.0 and 3.0 mg/kg significantly reduced methamphetamine self-administration by 26 and 36%, respectively, but did not alter food reinforcement at any dose tested. These data suggest that mGluR5 receptors are involved in the reinforcing effects of methamphetamine, and that antagonists of this receptor may serve as novel pharmacologic agents for the treatment of addiction to methamphetamine.

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Involvement of glutamate-mediated processes in AMPH reinforcement and SA has been welldocumented. For instance, mGlu 5 receptor antagonists produce a dose-dependent decrease in METH SA without affecting food reinforcement, suggesting that mGlu 5 receptors are involved in the reinforcing effects of METH, but not natural rewards (Osborne and Olive, 2008). Similar effects have been reported with the mGlu 2/3 antagonist LY379268 (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid) (Crawford et al, 2013;Kufahl et al, 2013).…”

Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

“…The results of preclinical studies employing antagonists for different glutamate receptors or transporters also support a necessary role for intact glutamate signaling in the manifestation of methamphetamine-seeking behavior (Fujio et al, 2005a;Gass et al, 2009;Kim and Jang, 1997;Miyatake et al, 2005;Nakagawa et al, 2005;Osborne and Olive, 2008). Further, systemic pretreatment with glutamate antagonists also blunts the capacity of non-contingent methamphetamine injections to elevate or sensitize striatal dopamine and/or protects against methamphetamine-induced dopamine toxicity, indicating an important role for glutamate transmission in regulating methamphetamineinduced neurochemical plasticity (Arai et al, 1996(Arai et al, , 1997Battaglia et al, 2002;Golembiowska et al, 2003;Ohmori et al, 1995Ohmori et al, , 1996Shimazoe et al, 2002).…”

“…Limited attention has been paid to the effects of methamphetamine on glutamate neurotransmission, however, a critical role of glutamate signaling in the 'addictive' properties of methamphetamine is supported by findings that both intravenous (IV) methamphetamine self-administration and cue-induced reinstatement of methamphetamine-seeking are blocked by mGluR5 antagonism in rats (Osborne and Olive, 2008). Moreover, an active role for glutamate in methamphetamine-induced behavioral plasticity has been implicated by two lines of research.…”

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

“…These compounds also inhibit the self-administration of other drugs of dependence such as cocaine 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 11 responding for drug rewards (Chiamulera et al 2001;Paterson et al 2003;Tessari et al 2004;Osborne and Olive 2008;Tronci et al 2010). In these studies, however, responding was generally studied using a fixed ratio paradigm.…”