Glucagon-Like Peptide-1 Analog Exendin-4 Ameliorates Cocaine-Mediated Behavior by Inhibiting Toll-Like Receptor 4 Signaling in Mice

Abstract

Exendin-4 (Ex4), a long-lasting glucagon-like peptide-1 analog, was reported to exert favourable actions on inhibiting cocaine-associated rewarding and reinforcing effects of drug in animal models of addiction. However, the therapeutic potential of different dose of GLP-1 receptor agonist Ex4 in different behavioral paradigms and the underlying pharmacological mechanisms of action are incompletely understood. Herein, we firstly investigated the effects of Ex4 on cocaine-induced condition place preference (CPP) as well as extinction and reinstatement in male C57BL/6J mice. Additionally, we sought to elucidate the underlying pharmacological mechanism of these actions of Ex4. The paradigm of cocaine-induced CPP was established using 20 mg/kg cocaine or saline alternately during conditioning, while the reinstatement paradigm was modeled using 10 mg/kg cocaine on the reinstatement day. Different dose of Ex4 was administrated intraperitoneally either during conditioning or during extinction state or only on the test day. To elucidate the molecular mechanism underlying the potential effects of Ex4 on maladaptive behaviors of cocaine, the TLR4-related inflammation within the hippocampus was observed by immunofluorescence staining, and the expression levels of toll-like receptor 4 (TLR4), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β were detected by Western blotting. As a consequence, systemic administration of different dose of Ex4 was sufficient to inhibit the acquisition and expression of cocaine-induced CPP, facilitate the extinction of cocaine-associated reward and attenuate reinstatement of cocaine-induced behavior. Furthermore, Ex4 treatment diminished expression levels of TLR4, TNF-α, and IL-1β, which were up-regulated by cocaine exposure. Altogether, our results indicated that Ex4 effectively ameliorated cocaine-induced behaviors likely through neurobiological mechanisms partly attributable to the inhibition of TLR4, TNF-α and IL-1β in mice. Consequently, our findings improved our understanding of the efficacy of Ex4 for the amelioration of cocaine-induced behavior and suggested that Ex4 may be applied as a drug candidate for cocaine addiction.

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

“…Additionally, the significant reinstatement of cocaine-induced CPP is induced after reexposure to a half dose of cocaine (10 mg/kg, i.p.). These results are in line with our previous study showing that 20 and 10 mg/kg were sufficient to produce CPP and reinstatement, respectively ( Zhu et al, 2021 ). Furthermore, this study also suggests that the systemic pretreatment with Ex4 after each extinction session significantly prevents the cocaine-priming reinstatement of the conditioned behavior in the study.…”

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

“…This is in line with a previous study indicating that memory retention could be disrupted after post-learning manipulations (Grecksch and Matthies, 1980). The expression levels of TLR4 within the hippocampus reactivated by cocaine were clearly inhibited by Ex4, similar to a previous study showing that Ex4 plays an anti-inflammatory role (Ajay et al, 2011;Zhu et al, 2021). Consequently, the GLP-1R agonist Ex4 is capable of modulating cocaine-related CPP memory, enhancing extinction, and weakening the cocaine-primed reinstatement by suppressing TLR4 over-expression within the hippocampus, similar to many studies revealing that extinction in substance abuse can be pharmacologically enhanced (Botreau et al, 2006;Paolone et al, 2009).…”

“…Recent literature indicated that GLP-1R agonist Ex4 appears highly promising in attenuating the rewarding and reinforcing effects of cocaine addiction (Hernandez and Schmidt, 2019 ; Zhu et al, 2021 ). For instance, systemic administration of Ex4 is believed to play a substantial role in cocaine dependence (Hernandez et al, 2019 ), such as attenuating cocaine-induced CPP, self-administration, and the cocaine-triggered relapse of drug-seeking in an animal model of cocaine use disorder (Engel and Jerlhag, 2014 ; Hayes and Schmidt, 2016 ; Hernandez et al, 2018 ; Hernandez and Schmidt, 2019 ).…”

Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder

“…Intriguingly, GLP-1RAs have received widespread attention in recent years due to their neuroprotective (Holst et al, 2011;Zhu et al, 2021) and anti-inflammatory effects (Hattori et al, 2010;Chaudhuri et al, 2012;Lee and Jun 2016). For example, exendin-4 has been reported to be effective in reducing inflammation indices, including TLR2, TLR4, NF-κβ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β (Chaudhuri et al, 2012;Kozela et al, 2017;Li et al, 2020), which have been heavily implicated in cocaine-related memories (Correia et al, 2020).…”