Effects of Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 on the Reinstatement of Cocaine-Mediated Conditioned Place Preference in Mice

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.

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

Frontiers in Systems Neuroscience ◽

10.3389/fnsys.2021.711750 ◽

2021 ◽

Vol 15 ◽

Author(s):

Changliang Zhu ◽

Tao Hong ◽

Hailiang Li ◽

Shucai Jiang ◽

Baorui Guo ◽

...

Keyword(s):

Receptor Agonist ◽

Place Preference ◽

Extinction Training ◽

Maladaptive Behavior ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Tlr4 Signaling ◽

Conditioned Behavior ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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.

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The novel dual glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 ( GLP ‐1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long‐acting GLP ‐1 receptor agonists

Diabetes Obesity and Metabolism ◽

10.1111/dom.14110 ◽

2020 ◽

Vol 22 (10) ◽

pp. 1886-1891 ◽

Cited By ~ 1

Author(s):

Shweta Urva ◽

Tamer Coskun ◽

Corina Loghin ◽

Xuewei Cui ◽

Emily Beebe ◽

...

Keyword(s):

Gastric Emptying ◽

Receptor Agonist ◽

The Novel ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Long Acting

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Cannabidiol prevents priming- and stress-induced reinstatement of the conditioned place preference induced by cocaine in mice

Journal of Psychopharmacology ◽

10.1177/0269881120965952 ◽

2021 ◽

pp. 026988112096595

Author(s):

Claudia Calpe-López ◽

Ani Gasparyan ◽

Francisco Navarrete ◽

Jorge Manzanares ◽

Jose Miñarro ◽

...

Keyword(s):

Gene Expression ◽

Ventral Tegmental Area ◽

Conditioned Place Preference ◽

Cannabis Sativa ◽

Social Defeat ◽

Place Preference ◽

Cocaine Seeking ◽

Ventral Tegmental ◽

Relative Gene ◽

Reinstatement Test

Background: Cocaine dependence is an important problem without any effective pharmacological treatment. Some preclinical studies have suggested that cannabidiol (CBD), a component of the Cannabis sativa plant, could be useful for the treatment of cocaine use disorders. Aims: This work aims to evaluate the ability of CBD to reduce priming- and stress-induced reinstatement of the conditioned place preference (CPP) induced by cocaine. Methods: Young adult CD-1 male mice were allocated to 10 groups ( n = 12/group), conditioned with cocaine (10 mg/kg) and exposed to extinction of CPP (two sessions per week). When extinction was achieved, each group received the corresponding treatment before the reinstatement test. In experiment 1, six groups were used: vehicle+saline (Veh+Sal), 5 mg/kg cocaine alone (Veh+Coc) or with CBD 30 or 60 mg/kg (CBD30+Coc, CBD60+Coc) and CBD alone (CBD30+Sal, CBD60+Sal). In experiment 2, four groups were used: exploration (Veh+Expl), social defeat (Veh+SD) and social defeat with CBD (CBD30+SD and CBD60+SD). Furthermore, the relative gene expression of the dopamine transporter (DAT) in the ventral tegmental area was measured. Results: All mice acquired cocaine CPP and extinguished it after three or four weeks. Only the groups treated with cocaine priming (Veh+Coc) or exposed to social defeat (Veh+SD) showed reinstatement of CPP. Interestingly, CBD itself did not induce reinstatement and blocked the reinstating effects of cocaine priming and social defeat. Furthermore, cocaine priming increased DAT gene expression in the ventral tegmental area and CBD completely reversed this effect. Conclusion: These results suggest that CBD could reduce reinstatement to cocaine seeking after a period of abstinence.

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