Abstract
A high percentage of relapse to compulsive cocaine-taking and cocaine-seeking behaviors following abstinence constitutes a major obstacle to the clinical treatment of cocaine addiction. Thus, there is a substantial need to develop effective pharmacotherapies for the prevention of cocaine relapse. The reinstatement paradigm is known as the most commonly used animal model to study relapse in abstinent human addicts. The primary aim of this study is to investigate the potential effects of systemic administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) on the cocaine- and stress-triggered reinstatement of cocaine-induced conditioned place preference (CPP) in male C57BL/6J mice. The biased CPP paradigm was induced by alternating administration of saline and cocaine (20 mg/kg), followed by extinction training and then reinstatement by either a cocaine prime (10 mg/kg) or exposure to swimming on the reinstatement test day. To examine the effects of Ex4 on the reinstatement, Ex4 was systemically administered 1 h after the daily extinction session. Additionally, we also explored the associated molecular basis of the behavioral effects of Ex4. The expression of nuclear factor κβ (NF-κβ) in the nucleus accumbens (NAc) was detected using Western blotting. As a result, all animals that were treated with cocaine during the conditioning period successfully acquired CPP, and their CPP response was extinguished after 8 extinction sessions. Furthermore, the animals that were exposed to cocaine or swimming on the reinstatement day showed a significant reinstatement of CPP. Interestingly, systemic pretreatment with Ex4 was sufficient to attenuate cocaine- and stress-primed reinstatement of cocaine-induced CPP. Additionally, the expression of NF-κβ, which was upregulated by cocaine, was normalized by Ex4 in the cocaine-experienced mice. Altogether, our study reveals the novel effect of Ex4 on the reinstatement of cocaine-induced CPP and suggests that GLP-1R agonists appear to be highly promising drugs in the treatment of cocaine use disorder.
Highlights
Recent epidemiological data from the World Drug Report indicate that substance use disorder is spreading widely and rapidly, causing about 585,000 deaths worldwide per year (UNODC, 2019)
A two-way rmANOVA followed by Dunnett’s multiple comparison test showed that there was no significant difference in conditioned place preference (CPP) scores compared with the Sal + Sal group (p > 0.05; n = 8 per group; Figure 1B), indicating that the cocaineinduced CPP response was completely extinguished
Two-way ANOVA suggested a significant difference in the time spent in the cocaine-paired chamber [F(3,28) = 21.82, p < 0.001; Figure 1C], and Tukey’s multiple comparison post hoc analysis showed that the Coc + Sal group developed a robust reinstatement of cocaine-induced CPP compared with the Sal + Sal group (p < 0.001) that was significantly attenuated by Ex4 (p < 0.001)
Summary
Recent epidemiological data from the World Drug Report indicate that substance use disorder is spreading widely and rapidly, causing about 585,000 deaths worldwide per year (UNODC, 2019). Cocaine abuse is characterized by a high rate of relapse following a long period of detoxification. Stressful life events and reexposure to the psychostimulants themselves are well known as two major stimuli for relapse to cocaine-associated behavior (Jaffe et al, 1989; O’Brien, 1997; Sinha et al, 1999). To date, the high relapse rate remains a major obstacle to the clinical treatment of cocaineaddicted individuals (O’Brien, 1997). Despite extensive efforts over the past decades to search for medications to treat cocaine addiction and reduce relapse, the effectiveness of available modulators has been reported to be limited. There is a substantial need for identifying more effective medications to treat cocaine use disorder and prevent relapse
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