# Arginine Metabolism and Adenosine Receptor Signals in the Cerebellum Contribute to Nicotine Withdrawal‐Induced Anxiety/Depression‐Like Behaviours

## TL;DR

This study finds that changes in arginine and purine metabolism in the cerebellum contribute to anxiety and depression-like behaviors during nicotine withdrawal, and that theobromine can help alleviate these symptoms.

## Contribution

The study identifies novel metabolic and signaling pathways in the cerebellum that contribute to nicotine withdrawal symptoms and suggests a potential treatment with theobromine.

## Key findings

- Enhanced purine metabolism and disrupted arginine metabolism in the cerebellum contribute to anxiety and depression-like behaviors during nicotine withdrawal.
- Treatment with theobromine alleviates these behaviors by inhibiting adenosine signaling and restoring arginine metabolism.

## Abstract

Recent studies have established a strong association between the cerebellum and various psychiatric disorders, as well as drug addiction and withdrawal processes. However, the mechanisms underlying the cerebellum's role in nicotine withdrawal symptoms have yet to be explored. In this study, we employed transcriptome sequencing, untargeted metabolomics and integrative multi‐omics analysis to elucidate the molecular mechanisms underlying nicotine withdrawal‐induced affective symptoms, specifically anxiety and depression‐like behaviours, within the cerebellum. Our findings demonstrate that enhanced purine metabolism and disrupted arginine metabolism in the cerebellum significantly contribute to the development of anxiety and depression‐like behaviours in mice undergoing nicotine withdrawal. Treatment with the non‐selective adenosine receptor antagonist, theobromine, markedly alleviates these behaviours. This mechanism likely involves inhibiting adenosine signalling and restoring arginine metabolism in the cerebellum.

This research indicates that enhanced purine metabolism and disrupted arginine metabolism contribute to the nicotine withdrawal‐induced anxiety and depression‐like behaviours in the cerebellum. Treatment with theobromine markedly alleviates these behaviours. The mechanism likely involves inhibiting adenosine signalling and restoring cAMP‐PKA, NO‐cGMP signalling and arginine metabolism in the cerebellum.