A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats

• Published in: Addiction biology Vol. 19; no. 2; pp. 195 - 209
• Main Authors: Keck, Thomas M., Zou, Mu-Fa, Bi, Guo-Hua, Zhang, Hai-Ying, Wang, Xiao-Fei, Yang, Hong-Ju, Srivastava, Ratika, Gardner, Eliot L., Xi, Zheng-Xiong, Newman, Amy Hauck
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.03.2014; John Wiley & Sons, Inc
• Subjects: Addiction; Allosteric Regulation; Analysis of Variance; Animals; Behavior; Binding, Competitive; Cocaine; Cocaine - administration & dosage; cue-induced cocaine seeking; Cues; Dopamine Uptake Inhibitors - administration & dosage; Dose-Response Relationship, Drug; Drug-Seeking Behavior - drug effects; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; HEK293 Cells; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; In Vitro Techniques; Infusions, Intravenous; Inhibitory Concentration 50; Male; MFZ 10-7; mGluR5; Motor Activity - drug effects; MTEP; Nitriles - pharmacology; Piperidines - chemistry; Piperidines - pharmacology; Pyridines - chemistry; Pyridines - pharmacology; Random Allocation; Rats; Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors; Receptor, Metabotropic Glutamate 5 - physiology; Reinforcement Schedule; reinstatement; Reward; Rodents; Secondary Prevention; Self Administration; Sucrose; Sucrose - administration & dosage; Thiazoles - chemistry; Thiazoles - pharmacology; MFZ 10-7; cue-induced cocaine seeking; reinstatement; self-administration; MTEP; Cocaine; sucrose; mGluR5
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12086

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. The mGluR5 negative allosteric modulators (NAMs) MPEP and MTEP are highly promising in treatment of addiction in experimental animals. However, their translational potential for use in humans is very low because of their off‐target effects and short half‐lives. Here, we report that MFZ 10‐7, a novel mGluR5 NAM, is more potent and selective than MPEP or MTEP in both in vitro binding and functional assays, and similarly effective as MTEP in attenuation of cocaine‐taking and cocaine‐seeking behavior in rats.