Fenobam sulfate inhibits cocaine-taking and cocaine-seeking behavior in rats: Implications for addiction treatment in humans

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. Objectives: 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. Results: 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. Conclusions: 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.