title: A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats.
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.
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse. NIH, DHHS, Baltimore, MD, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keck
authors.forename: Mu-Fa
authors.initials: MF
authors.lastname: Zou
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Bi
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zhang
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Wang
authors.forename: Hong-Ju
authors.initials: HJ
authors.lastname: Yang
authors.forename: Ratika
authors.initials: R
authors.lastname: Srivastava
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000494:Allosteric Regulation; D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D003042:Cocaine / Q000008:administration & dosage*; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D020128:Inhibitory Concentration 50; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000502:physiology; D012055:Reinforcement Schedule; D012201:Reward; D055502:Secondary Prevention; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C541428:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)piperidine; C000593127:3-fluoro-5-((6-methylpyridin-2-yl)ethynyl)benzonitrile; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D009570:Nitriles; D010880:Piperidines; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; C032794:fenobam; D013395:Sucrose; C121465:6-methyl-2-(phenylethynyl)pyridine; D003042:Cocaine
keywords: Cocaine; MFZ 10-7; MTEP; cue-induced cocaine seeking; mGluR5; reinstatement; self-administration; sucrose