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Researchers discover that glutamine synthetase, an enzyme in astrocytes, regulates locomotor sensitization after repeated nicotine exposure. Credit: Prof. Eun Sang Choe / Pusan National University, Republic of Korea

Nicotine addiction remains one of the most persistent public health challenges worldwide, driven by brain changes that reinforce repeated use and make quitting extremely difficult. For decades, explanations focused mostly on neurons, but mounting evidence points to other brain cells playing an active role in addictive behavior.

Astrocytes’ role in nicotine addiction

A team led by Professor Eun Sang Choe at Pusan National University (Republic of Korea) has identified a mechanism by which astrocytes contribute to nicotine-induced brain changes. The study, published in Acta Pharmaceutica Sinica B, implicates astrocytic glutamine synthetase (GS)—an enzyme central to regulating glutamate, the brain’s main excitatory neurotransmitter—in driving behavioral sensitization to nicotine.

“Most of the studies on nicotine addiction traditionally focus on neurons, while neglecting the role of glial cells. Our innovative study demonstrates that astrocytes interact with neurons within the brain’s reward system to regulate nicotine-dependent behavior, advancing the current understanding of nicotine addiction,” says Prof. Choe.

Key findings

Using repeated nicotine injections in rat models, the researchers found nicotine activated α7 nicotinic acetylcholine receptors on astrocytes in the caudate and putamen. This receptor stimulation triggered a surge in intracellular calcium, which in turn activated phosphorylated c-Jun N-terminal kinase (pJNK), a signaling molecule responsive to cellular stress and drug exposure.

Activated JNK then interacted with metabotropic glutamate receptor 1a (mGluR1a), increasing GS activity and engaging the glutamate–glutamine pathway. The result was enhanced glutamatergic neurotransmission and increased locomotor sensitization.

Activation of glutamine synthetase by stimulating the JNK–mGluR1a interaction in astrocytes of the CPu after nicotine exposure may be necessary for locomotor sensitization via elevation of glutamatergic neurotransmission. Credit: Acta Pharmaceutica Sinica B (2025). DOI: 10.1016/j.apsb.2025.09.038

To test causality, the team used a custom-designed inhibitory peptide to block the pJNK–mGluR1a interaction. When administered directly into the caudate and putamen of nicotine-exposed rats, the peptide markedly reduced the nicotine-induced rise in GS activity and attenuated locomotor sensitization, showing that astrocytic signaling is a key driver of these behavioral effects.

Implications

These results underscore the importance of neuron–glia communication in nicotine dependence. While disrupted glutamate signaling is already recognized in nicotine addiction, this study shows astrocytes actively participate in the molecular cascade that reinforces repeated nicotine use. The work is preclinical, so direct human application remains uncertain, but it opens new avenues for research into addiction mechanisms and potential therapeutic targets.

“While clinical translation of this research will take time and direct human application is uncertain, this work deepens our understanding of nicotine addiction, paving the way for development of therapeutic strategies ultimately supporting smoking-cessation efforts,” concludes Prof. Choe.

More information: Ju Hwan Yang et al, Glutamine synthetase in astrocytes of the caudate and putamen is responsible for locomotor sensitization after nicotine exposure, Acta Pharmaceutica Sinica B (2025). DOI: 10.1016/j.apsb.2025.09.038

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