The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse.
The purpose of the present study was to explore whether MPEP-induced decreases in nicotine and cocaine self-administration reflect attenuation of the reinforcing and incentive motivational effects of nicotine and cocaine. The effects of MPEP on breaking points maintained by nicotine, cocaine or food were assessed using a progressive ratio schedule of reinforcement. Breaking points obtained under such schedules are postulated to reflect both the reinforcing and incentive motivational properties of reinforcers.
Rats were allowed to respond for nicotine (0.05 mg/kg per infusion, free base), cocaine (0.18 mg/kg per infusion, salt), or food (45 mg pellets) under a progressive ratio schedule of reinforcement. After establishing stable and equivalent levels of responding for all three reinforcers, rats underwent one test session where no rewards were presented to assess the effects of 1-day extinction, similar to 1-day pharmacological-induced extinction, on performance in this schedule. Subsequently, rats were again allowed to respond for nicotine, cocaine or food until reestablishment of stable levels of responding. Then, MPEP (1-9 mg/kg) was administered intraperitoneally according to a within-subjects Latin square design, 30 min prior to the testing sessions.
Responding in the absence of a primary reinforcer was significantly decreased compared to responding under baseline conditions. Further, MPEP decreased break points maintained by nicotine, cocaine and food.
The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.
"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, 2003; Liechti and Markou, 2007; Palmatier et al, 2008; Paterson and Markou, 2005; "
"(MTEP), as well as fenobam significantly inhibit behaviors associated with addiction in experimental animals, including cocaine self-administration (Tessari et al. 2004; Kenny et al. 2005; Lee et al. 2005; Paterson & Markou 2005; Martin-Fardon et al. 2009; Keck et al. 2013), cocaine-induced conditioned place preference (McGeehan & Olive 2003; Herzig & Schmidt 2004), cocaine-induced hyperactivity (McGeehan, Janak & Olive 2004), and cocaine-, cue-or stress-induced reinstatement of drug-seeking behavior (Lee et al. 2005; Backström & Hyytiä 2006; Kumaresan et al. 2009; Martin-Fardon & Weiss 2012; Keck et al. 2013; Wang et al. 2013). These data strongly suggest that mGluR5 plays an important role in cocaine abuse and addiction and that mGluR5 NAMs may have potential for the treatment of cocaine addiction in humans (Heidbreder et al. 2003; Olive et al. 2005). "
[Show abstract][Hide abstract] ABSTRACT: Pre-clinical studies suggest that negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5), including 2-methyl-6-(phenylethynyl)pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and fenobam are highly effective in attenuating drug-taking and drug-seeking behaviors. However, both MPEP and MTEP have no translational potential for use in humans because of their off-target effects and short half-lives. Here, we report that 3-fluoro-5-[(6-methylpyridin-2-yl)ethynyl]benzonitrile (MFZ 10-7), a novel mGluR5 NAM, is more potent and selective than MPEP, MTEP and fenobam in both in vitro binding and functional assays. Similar to MTEP, intraperitoneal administration of MFZ 10-7 inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Although MFZ 10-7 and MTEP lowered the rate of oral sucrose self-administration, they did not alter total sucrose intake. Further, MFZ 10-7 appeared to be more potent than MTEP in inducing downward shifts in the cocaine dose-response curve, but less effective than MTEP in attenuating sucrose-induced reinstatement of sucrose-seeking behavior. MFZ 10-7 and MTEP had no effect on basal locomotor behavior. These findings not only provide additional evidence supporting an important role for mGluR5 in cocaine reward and addiction, but also introduce a new tool for both in vitro and in vivo investigations with which to further characterize this role.
"In addition to inhibition of cocaine self-administration, fenobam sulfate also inhibited sucrose self-administration and sucrose-induced reinstatement. This is consistent with previous reports that MPEP or MTEP decrease food-taking behavior in rats and non-human primates (Paterson and Markou 2005; Platt et al. 2008) and with a recent report that fenobam free base inhibits food-and sucrose-induced reinstatement of reward-seeking behavior (Watterson et al. 2013). We note, however, that in the present study, fenobam sulfate appears to be more effective in inhibiting cocainetaking and cocaine-seeking behavior than in inhibiting sucrose-taking and sucrose-seeking behavior (Figs. "
[Show abstract][Hide abstract] ABSTRACT: Rationale:
The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be critically involved in drug reward and addiction. Because the mGluR5 negative allosteric modulators (NAMs) 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) significantly inhibit addictivelike behaviors of cocaine and other drugs of abuse in experimental animals, it has been suggested that mGluR5 NAMs may have translational potential for treatment of addiction in humans. However, neither MPEP nor MTEP have been evaluated in humans due to their off-target actions and rapid metabolism.
Herein, we evaluate a potential candidate for translational addiction research: a new sulfate salt formulation of fenobam, a selective mGluR5 NAM that has been investigated in humans.
In rats, fenobam sulfate had superior pharmacokinetics compared to the free base, with improved maximal plasma concentration (C max) and longer half life. Oral (p.o.) administration of fenobam sulfate (30 or 60 mg/kg) inhibited intravenous (i.v.) cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior, and cocaine-associated cue-induced cocaine-seeking behavior in rats. Fenobam sulfate also inhibited p.o. sucrose self-administration and sucrose-induced reinstatement of sucrose-seeking behavior, but had no effect on locomotion.
This study provides additional support for the role of mGluR5 signaling in cocaine addiction and suggests that fenobam sulfate may have translational potential in medication development for the treatment of cocaine addiction in humans.
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