Nicotine addiction continues to be a significant global public health concern, largely due to changes in the brain that make quitting difficult. Historically, research has focused on neurons to explain these changes, but recent studies suggest that other types of brain cells may also play a critical role.
A team led by Professor Eun Sang Choe from the Department of Biological Sciences at Pusan National University in South Korea has identified how astrocytes, a type of glial cell, contribute to nicotine-induced changes in the brain. The study, published in Acta Pharmaceutica Sinica B on September 25, 2025, details a mechanism involving the enzyme glutamine synthetase (GS), which regulates glutamate—the main excitatory neurotransmitter in the brain.
"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," said Prof. Choe.
The researchers conducted experiments using rat models injected repeatedly with nicotine. They observed that nicotine activated α7 nicotinic acetylcholine receptors located on astrocytes in specific regions of the brain known as the caudate and putamen. This activation caused an increase in intracellular calcium levels and triggered phosphorylated c-Jun N-terminal kinase (pJNK), a molecule responsive to cellular stress and drug exposure. Activated JNK then interacted with metabotropic glutamate receptor 1a (mGluR1a), which increased GS activity and stimulated the glutamate-glutamine pathway—leading to greater locomotor sensitization.
To test this pathway further, scientists developed an inhibitory peptide designed to block pJNK’s interaction with mGluR1a. When this peptide was administered directly into the caudate and putamen regions of rats exposed to nicotine, it significantly reduced GS activity and dampened behavioral sensitization associated with repeated nicotine use.
These results indicate that communication between neurons and glial cells is essential for understanding addictive behaviors linked to nicotine. The findings suggest that astrocytic signaling is not just supportive but actively shapes responses to drugs like nicotine.
"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," concluded Prof. Choe.
