Paul W Czoty1, Bruce E Blough2, Antonio Landavazo2, Michael A Nader3. 1. Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. pczoty@wakehealth.edu. 2. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA. 3. Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
Abstract
RATIONALE: Because chronic cocaine exposure produces profound effects on brain glutamate function, this system has been investigated as a target for novel medications for cocaine use disorder. Studies in animal models have provided encouraging results for drugs that target metabotropic glutamate receptors (mGluR), particularly group II mGluRs which includes mGluR2 and mGluR3 receptors. OBJECTIVE: The present study examined the effects of the mGluR2/3 receptor-selective agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), in male rhesus monkeys self-administering cocaine under two procedures that assess the strength of cocaine as a reinforcer. METHODS AND RESULTS: In four monkeys, acute effects of LY379268 on food and cocaine self-administration were characterized using a multiple 10-response fixed-ratio food, progressive-ratio cocaine schedule of reinforcement. Maximum injections were delivered when the available cocaine dose was 0.01-0.1 mg/kg. When monkeys self-administered 0.03 mg/kg per injection cocaine, LY379268 (0.001-0.56 mg/kg, i.v.), increased cocaine injections and disrupted food-maintained responding. Another group of monkeys (n = 3) responded under a food-cocaine choice procedure in which a dose-effect curve for self-administered cocaine (0.0, 0.003-0.1 mg/kg per injection) was generated daily. Acute LY379268 (0.01-0.1 mg.kg, i.v.) produced a shift in allocation of responding towards cocaine without affecting the total reinforcers delivered. When treatment was extended to 5 consecutive days, tolerance developed to LY379268-induced increases in cocaine choice. CONCLUSIONS: These data from two complimentary nonhuman primate models of cocaine use disorder are consistently negative with respect to the potential of LY379268 as a pharmacotherapy for reducing ongoing cocaine use.
RATIONALE: Because chronic cocaine exposure produces profound effects on brain glutamate function, this system has been investigated as a target for novel medications for cocaine use disorder. Studies in animal models have provided encouraging results for drugs that target metabotropic glutamate receptors (mGluR), particularly group II mGluRs which includes mGluR2 and mGluR3 receptors. OBJECTIVE: The present study examined the effects of the mGluR2/3 receptor-selective agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), in male rhesus monkeys self-administering cocaine under two procedures that assess the strength of cocaine as a reinforcer. METHODS AND RESULTS: In four monkeys, acute effects of LY379268 on food and cocaine self-administration were characterized using a multiple 10-response fixed-ratio food, progressive-ratio cocaine schedule of reinforcement. Maximum injections were delivered when the available cocaine dose was 0.01-0.1 mg/kg. When monkeys self-administered 0.03 mg/kg per injection cocaine, LY379268 (0.001-0.56 mg/kg, i.v.), increased cocaine injections and disrupted food-maintained responding. Another group of monkeys (n = 3) responded under a food-cocaine choice procedure in which a dose-effect curve for self-administered cocaine (0.0, 0.003-0.1 mg/kg per injection) was generated daily. Acute LY379268 (0.01-0.1 mg.kg, i.v.) produced a shift in allocation of responding towards cocaine without affecting the total reinforcers delivered. When treatment was extended to 5 consecutive days, tolerance developed to LY379268-induced increases in cocaine choice. CONCLUSIONS: These data from two complimentary nonhuman primate models of cocaine use disorder are consistently negative with respect to the potential of LY379268 as a pharmacotherapy for reducing ongoing cocaine use.
Authors: Peter R Kufahl; Lucas R Watterson; Natali E Nemirovsky; Lauren E Hood; Angel Villa; Casey Halstengard; Nicholas Zautra; M Foster Olive Journal: Neuropharmacology Date: 2012-05-31 Impact factor: 5.250