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

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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.

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.

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Acknowledgments

This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. T.M.K. was supported by an NIH Postdoctoral Intramural Research Training Associate (IRTA) Fellowship. Pharmacokinetic data was provided under NIDA Contract, N01DA-9-8883. We thank Drs. Phil Skolnick and Amrat Patel, Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, for providing the fenobam free base and fenobam sulfate, helpful discussions, and critical reading of this manuscript.

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Authors and Affiliations

  1. Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, Baltimore, MD, 21224, USA

    Thomas M. Keck & Amy Hauck Newman

  2. Neuropsychopharmacology Section, Chemical Biology Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, 21224, USA

    Hong-Ju Yang, Guo-Hua Bi, Hai-Ying Zhang, Ratika Srivastava, Eliot L. Gardner & Zheng-Xiong Xi

  3. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, 94143, USA

    Yong Huang

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  1. Thomas M. Keck
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  2. Hong-Ju Yang
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  9. Zheng-Xiong Xi
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Correspondence to Amy Hauck Newman or Zheng-Xiong Xi.

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Keck, T.M., Yang, HJ., Bi, GH. et al. Fenobam sulfate inhibits cocaine-taking and cocaine-seeking behavior in rats: implications for addiction treatment in humans. Psychopharmacology 229, 253–265 (2013). https://doi.org/10.1007/s00213-013-3106-9

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