Abstract
Novel molecular targets are needed to develop new medications for the treatment of cocaine addiction. Here we investigated a role for glucagon-like peptide-1 (GLP-1) receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. We showed that peripheral administration of the GLP-1 receptor agonist exendin-4 dose dependently reduced cocaine seeking in rats at doses that did not affect ad libitum food intake, meal patterns or body weight. We also demonstrated that systemic exendin-4 penetrated the brain where it putatively bound receptors on both neurons and astrocytes in the ventral tegmental area (VTA). The effects of systemic exendin-4 on cocaine reinstatement were attenuated in rats pretreated with intra-VTA infusions of the GLP-1 receptor antagonist exendin-(9–39), indicating that the suppressive effects of systemic exendin-4 on cocaine seeking were due, in part, to activation of GLP-1 receptors in the VTA. Consistent with these effects, infusions of exendin-4 directly into the VTA reduced cocaine seeking. Finally, extinction following cocaine self-administration was associated with decreased preproglucagon mRNA expression in the caudal brainstem. Thus, our study demonstrated a novel role for GLP-1 receptors in the reinstatement of cocaine-seeking behavior and identified behaviorally relevant doses of a GLP-1 receptor agonist that selectively reduced cocaine seeking and did not produce adverse effects.
Highlights
One hallmark of cocaine addiction is the high rate of relapse to compulsive drug use during periods of abstinence [1]
While peripheral administration of 3.0 μg/kg fluoro-Ex-4 significantly attenuated cocaine seeking, one could argue that the effects of fluoro-Ex-4 on drug seeking were due to malaise-like effects as previous studies have shown that an acute injection of 3.0 μg/kg exendin-4 produces a mild pica response and reduces food intake and body weight in rats [20, 21]
Administration of exendin-4 directly into the ventral tegmental area (VTA) dose dependently attenuated cocaine seeking in rats To determine whether increased activation of VTA glucagon-like peptide-1 (GLP-1) receptors during extinction is sufficient to attenuate cocaine seeking, exendin-4 was infused directly into the VTA 10 min prior to a cocaine priming-induced reinstatement test session
Summary
One hallmark of cocaine addiction is the high rate of relapse to compulsive drug use during periods of abstinence [1]. The most difficult aspect of treating cocaine addiction is preventing relapse [2]. GLP-1 receptor ligands are FDA-approved for treating type II diabetes mellitus and obesity based on their ability to increase insulin production and reduce food intake [5,6,7,8]. A growing literature indicates that peripheral administration of GLP-1 receptor agonists attenuates drug-associated behavioral responses including cocaine-induced conditioned place preference (CPP) and the locomotor-activating effects of cocaine [9,10,11]. No studies to date have examined the efficacy of GLP-1 receptor agonists to reduce the reinstatement of cocaine-seeking behavior, an animal model of relapse [12, 13]
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