Glucagon-Like Peptide-1 Agonist Exendin-4 Facilitates the Extinction of Cocaine-Induced Condition Place Preference.

Changliang Zhu,Shucai Jiang,Tao Sun,Yangyang Wang,Lei Wang,Tao Hong,Baorui Guo,Feng Wang,Yu Sun,Caibin Gao,Hailiang Li,Din Wan,Jiangwei Ding

doi:10.3389/fnsys.2021.711750

Abstract

Accumulating studies suggest that the glucagon-like peptide-1 receptor agonist exendin-4 (Ex4) and toll-like receptor 4 (TLR4) play a pivotal role in the maladaptive behavior of cocaine. However, few studies have assessed whether Ex4 can facilitate the extinction of drug-associated behavior and attenuate the reinstatement of cocaine-induced condition place preference (CPP) in mice. The main objective of the present study was to evaluate Ex4’s ability to regulate the extinction and reinstatement of cocaine-induced CPP. C57BL/6 mice were conditioned to either cocaine (20 mg/kg) or an equivalent volume of saline to establish a cocaine-mediated CPP paradigm. To investigate the potential effects of Ex4 on extinction, animals received an intraperitoneal injection of Ex4 either immediately or 6 h after each extinction or only on the test day. The persistence of extinction was measured using the reinstatement paradigm evoked by 10 mg/kg of cocaine. To explore the possible impacts of Ex4 and neuroinflammation on cocaine, the expression levels of TLR4 within the hippocampus was detected using western blotting. As a result, we found that systemic administration of Ex4 immediately after each extinction training, instead of 6 h after each extinction and on the day of extinction test, was capable of facilitating extinction in the confined or non-confined CPP extinction paradigms and blocking the cocaine-primed reinstatement of cocaine-induced CPP. Additionally, we also observed that Ex4 was competent to alleviate TLR4 signaling that has been up-regulated by cocaine. Altogether, our findings indicated that the combination of Ex4 with daily extinction training was sufficient to facilitate extinction of the conditioned behavior, attenuate reinstatement of cocaine-induced CPP and inhibit TLR4 signaling. Thus, Ex4 deserves further investigation as a potential intervention for the treatment of cocaine use disorder.

Highlights

Cocaine addiction is a chronic brain disorder characterized by a high proportion of relapse to compulsive behavior of cocaine intake even following a prolonged period of detoxification (Koob and Volkow, 2016)
These results suggested that an acute single administration of Ex4 on the extinction test day can not enhance the confined extinction of cocaine-induced Condition Place Preference (CPP)
We demonstrated the vital role of glucagon-like peptide-1 receptor agonist exendin-4 (Ex4) and toll-like receptor 4 (TLR4) in the extinction and reinstatement of cocaine-induced conditioned place preference (CPP)

Summary

Introduction

Cocaine addiction is a chronic brain disorder characterized by a high proportion of relapse to compulsive behavior of cocaine intake even following a prolonged period of detoxification (Koob and Volkow, 2016). Extinction training is considered as an active process that results in a progressive decline in acquired reactions It produces the normal formation of learning and memories that predicts no more delivery of addictive drugs with rewarding and pleasurable properties, thereby competing against the expression of original drug-related memories to control behavior (Marlatt, 1990; Millan et al, 2011; McNally, 2014; Chesworth and Corbit, 2015). It has been demonstrated that extinction can lead to the suppression of the original drug-related memories (Marlatt, 1990; Millan et al, 2011; McNally, 2014), thereby reducing the risk of relapse (Heather and Bradley, 1990) Taken together, these data support that weakening the drug-context memories using extinction training effectively reduces the susceptibility of relapse triggered by drug-context memories (Torregrossa and Taylor, 2016)

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