Effects of the mGluR2/3 agonist LY379268, alone and in combination with monoamineenhancing drugs, on cocaine self‐administration in rhesus monkeys

Abstract

Cocaine addiction persists as a major public health problem but still lacks any FDA‐approved pharmacotherapies. Wake Forest's Center for the Neurobiology of Drug Abuse Treatment (CNAT) has demonstrated the effectiveness of ‘agonist medications’ such as the monoamine releaser phenmetrazine (PM) and its pro‐drug phendimetrazine (PDM) to decrease cocaine use in animal models. CNAT investigators have hypothesized that combination of a dopamine‐enhancing drug like PM/PDM with a drug with a different pharmacological and/or behavioral mechanism may display enhanced effectiveness and represent a promising pharmacotherapeutic approach to treating cocaine use disorder. The present studies characterized the effects of the mGluR2/3 receptor agonist LY379268, alone and in combination with daily PDM or the dopamine transporter inhibitor methylphenidate (MPD) on cocaine reinforcement in rhesus monkeys. In one experiment (n=4), a multiple schedule was used in which food reinforcers were available in the first component under a fixed‐ratio schedule of reinforcement and cocaine self‐administration was studied under a progressive‐ratio schedule. A second study (n=4) used a food‐cocaine choice procedure in which a complete cocaine dose‐effect curve was generated each day. Effects of acute and chronic LY379268 were studied. Under the multiple schedule, acute LY379268 decreased food‐but not cocaine‐maintained responding; when administered chronically (as an i.v. injection) during chronic oral PDM treatment, a drug combination that persistently decreased cocaine self‐administration was found in only one of four subjects. Under the choice procedure, LY379268 increased the reinforcing strength of cocaine relative to food. After 5 days of treatment, tolerance developed to this effect in a dose‐related manner but at no point were decreases in cocaine choice observed. Finally, when chronic LY379268 was administered in combination with chronic oral PDM or chronic MPD (via subcutaneous osmotic pump), dose combinations were observed that modestly decreased cocaine choice in two of four monkeys. Although some results were positive, taken together these studies, which used highly translational nonhuman primate models of cocaine use disorder, do not support the effectiveness of LY 279638 alone or in combination with agonist medications.Support or Funding InformationP50 DA06634This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.