Generality of the relapse phenomenon: Reinstatement of food vs. brain stimulation reinforced behavior and its modulation by mGlu5 receptor blockade

William Joseph Addison Eiler, Purdue University

Abstract

One of the most formidable problems in the treatment of addiction is the high rate of relapse. Although there has been a tremendous amount of work on this problem with respect to drug addiction, little work has been done to establish the generality of the relapse phenomenon across reinforcing events. In this study, a novel animal model of reinstatement was developed and then utilized to evaluate the generality of the relapse phenomenon to reinforcers other than drugs of abuse. Male Sprague-Dawley rats were trained under this reinstatement paradigm in which every lever press produced a light and tone conjointly paired temporally with either a 45mg food pellet or the stimulation of the medial forebrain bundle (MFB). After establishment of stable responding, behavior was extinguished under conditions in which lever responses produced neither reinforcer nor reinforcer-associated stimuli. Responding was then assessed under reinstatement conditions in which all responses produced the reinforcer-associated stimuli and the first three responses of every 5-minute bin produced the associated stimuli along with either a food pellet or MFB stimulation. Since recent studies have suggested that glutamate neurotransmission via mGlu5 receptors might mediate relapse behavior, the effects of the mGlu5 antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[2-methyl-1, 3-thiazol-4-yl) ethynyl]-pyridine (MTEP) on reinstatement were studied under this paradigm. These effects were directly compared to the behavior of another group of rats which had never undergone extinction and in which every response produced both the reinforcer and reinforcer-associated stimuli. Both mGlu5 receptor antagonists significantly reduced reinstatement of extinguished responses for both reinforcers at doses without significant effect on non-extinguished responses demonstrating behavioral specificity of the drug effects. The effect of MTEP on reinstatement and maintenance under a progressive ratio schedule of reinforcement was also examined with the mGlu5 antagonist attenuating reinstatement at doses that did not affect maintained behavior. Additional experiments with food as the reinforcer evaluated the effect of training (continuous vs. intermittent reinforcement) and abstinence (extinction vs. incubation) on reinstatement responding following the administration of MTEP with the subsequent mGlu5 blockade reducing responding under all conditions. Pharmacological specificity of the relapse-attenuating effects of mGlu5 antagonists was established through comparison to effects of other compounds including d-amphetamine and naltrexone and was found not to alter reinstatement. In contrast, the CB1 receptor inverse agonist rimonabant and the mGlu2/3 agonist, 2-oxabicyclo[3.1.0] hexane-4,6-dicarboxylic acid, 4-amino (1R,4R,5S,6R) (LY379268) did selectively attenuate reinstatement, a finding consistent with their known pharmacology with respect to relapse. Finally, transgenic mGlu5 knock-out mice were evaluated under a reinstatement paradigm to further determine the role of the mGlu5 receptor in relapse behavior. The mGlu5 knock-out mice displayed reduced levels of reinstatement, an effect observed in their wild type littermates following a 30.0mg/kg dose of MTEP. The results of the current study not only demonstrate a role of mGlu5, mGlu2/3 and cannabinoid CB1 receptors in the control of relapse behavior, but lend support to the assertion that the relapse phenomenon generalizes to non-pharmacological reinforcers. Given the homologous findings reported with these mechanisms here and under other conditions of response reinstatement, the currently reported methods are given behavioral and pharmacological validation. These findings have implications for the discovery and development of pharmacological treatment options for a range of addictive behaviors that impact disease states (e.g., drug abuse, obesity disorders, pathological gambling, compulsive shopping, etc.).

Degree

Ph.D.

Subject Area

Psychobiology

COinS