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

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

doi:10.3389/fnsys.2021.711750

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

Front Syst Neurosci. 2021 Nov 24:15:711750. doi: 10.3389/fnsys.2021.711750. eCollection 2021.

Authors

Changliang Zhu^{1

2}, Tao Hong³, Hailiang Li², Shucai Jiang^{1

2}, Baorui Guo², Lei Wang², Jiangwei Ding², Caibin Gao^{1

2}, Yu Sun², Tao Sun^{1

2}, Feng Wang^{2

4}, Yangyang Wang², Din Wan¹

Affiliations

¹ Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China.
² Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China.
³ Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China.
⁴ Department of Neurosurgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

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.

Keywords: cocaine; condition place preference; exendin-4; extinction; reinstatement; toll-like receptor 4.