Semaglutide demonstrated differentiated efficacies in preclinical models of alcohol and substance use disorders in rats

Introduction

Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as potential modulators of the substance use disorders. However, the effects of semaglutide on distinct classes of abused substances, such as alcohol and psychostimulants, remains incompletely characterized.

Aims

This study aims to systematically evaluate the effects of semaglutide on preclinical models of alcohol and stimulant use disorders in rats.

Methods

The alcohol addictive behavior was assessed using the intermittent access to two-bottle choice (IA2BC) of alcohol drinking model in adult male Wistar rats. The 24-hour intake of both 20% alcohol and water were recorded, and the alcohol preference was calculated as the ratio of the 20% alcohol intake to the total fluid intake. The cocaine addiction was evaluated using the conditioned place preference (CPP) paradigm in adult male SD rats, and the CPP score was calculated as the time difference between animals spend in the drug paired chamber after conditioning and before conditioning. Data are presented as mean ± SEM. Ordinary one-way or repeated measures two-ways ANOVAs with appropriate post -hoc analysis were performed accordingly.

Results

After an 8-week IA2BC of alcohol drinking training, the 24-hour alcohol intake and alcohol preference of the rats were significantly increased compared to those of at the beginning of the training. Compared to vehicle treatment, acute single dose administration of both 0.02mg/kg and 0.04mg/kg semaglutide significantly reduced the 24-hour alcohol intake and alcohol preference of the rats. In addition, the total fluid intake exhibited no significant difference between vehicle and 0.02mg/kg semaglutide treated group, indicating a specific suppression of alcohol intake by semaglutide.

In the CPP paradigm, compared to vehicle treatment, acute single dose administration of 0.03mg/kg semaglutide 1-hour before the post-test significantly suppressed the cocaine CPP expression of rats after an 8-day cocaine conditioning. And compared to previous vehicle treatment, previous semaglutide treatment showed more robust effect on the extinction of cocaine CPP in rats. However, prime with cocaine after extinction significantly reinstated the cocaine CPP in both groups without statistical difference. On the other hand, chronic treatment with 0.03mg/kg semaglutide once daily for 3 days didn’t significantly affect cocaine CPP expression. Nonetheless, compared to previous vehicle treatment, previous semaglutide treatment showed more robust effect on the extinction of cocaine CPP in rats, although not statistically significant. And prime with cocaine after extinction induced a weaker yet without statistically significant reinstatement of the cocaine CPP in rats with previous chronic semaglutide treatment, compared to that with previous vehicle treatment.

Conclusions

These findings demonstrated that acute administration of semaglutide could effectively suppress the 24-hour alcohol intake and alcohol preference in rats. Similarly, acute administration of semaglutide significantly suppressed with the expression and extinction, but not reinstatement, of cocaine CPP in rats. Our ongoing investigation on the effect of semaglutide on regulating cocaine induced self-administration in rats will provide further evidence for the role of semaglutide in substance use disorders. Taken together, these preclinical data support semaglutide as potential therapeutics for substance use disorders, especially alcohol use disorder.

References

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