Summary: New research shows that astrocytes play an active role in nicotine-induced brain changes, challenging the old neuron-centered view of addiction. Nicotine stimulates astrocyte receptors, triggering signaling cascades that increase glutamine synthetase activity and amplify glutamate-related pathways.
These molecular changes strengthen locomotor sensitization, a hallmark of addiction-like neural adaptation. By blocking a critical astrocytic signaling interaction, the researchers were able to reduce these behavioral effects, pointing toward new long-term directions for addiction treatment.
Key facts
Astrocyte activation: Nicotine triggers calcium signaling in astrocytes, leading to activation of pJNK and increased glutamine synthetase activity. Glutamate pathway: These changes amplify the glutamate-glutamine cycle, reinforcing neuronal adaptations related to addiction. Therapeutic potential: Blockade of astrocytic signaling reduced nicotine-induced sensitization in rats, suggesting new targets for intervention.
Source: Pusan National University
Nicotine addiction remains one of the most persistent public health challenges worldwide, driven by changes in the brain that reinforce repeated use and make quitting extremely difficult.
For decades, scientists have focused primarily on neurons to explain how these changes occur. But growing evidence suggests that other brain cells may play a much more active role in shaping addictive behavior than previously thought.
Taking advantage of this shift in understanding, a team of researchers led by Professor Eun Sang Choe from the Department of Biological Sciences at Pusan National University, Republic of Korea, has discovered how astrocytes actively contribute to nicotine-induced brain changes, revealing a previously overlooked mechanism involving astrocytic glutamine synthetase (GS). GS is an essential enzyme for regulating glutamate, the brain’s main excitatory neurotransmitter.
The study was published online in the journal Acta Pharmaceutica Sinica B on September 25, 2025.
“Most studies on nicotine addiction traditionally focus on neurons, neglecting the role of glial cells. Our groundbreaking study demonstrates that astrocytes interact with neurons within the brain’s reward system to regulate nicotine-dependent behavior, advancing current understanding of nicotine addiction,” says Professor Choe.
In this study, the researchers repeatedly injected rat models with nicotine and found that nicotine exposure stimulated α7 nicotinic acetylcholine receptors in astrocytes in the caudate and putamen region of the brain, initiating an increase in intracellular calcium.
This increase in calcium led to the activation of phosphorylated c-Jun N-terminal kinase (pJNK), a signaling molecule known to respond to cellular stress and drug exposure. Once activated, JNK further interacted with metabotropic glutamate receptor 1a (mGluR1a), increasing GS activity and activating the glutamate-glutamine pathway, leading to increased locomotor sensitization.
A custom-designed inhibitory peptide was used to block the interaction between pJNK and mGluR1a. When this peptide was administered directly into the caudate and putamen of rats repeatedly exposed to nicotine, the usual increase in GS activity was significantly reduced. Behaviorally, this intervention decreased locomotor sensitization, demonstrating that astrocytic signaling is a key driver of nicotine-induced changes in the brain.
These findings open new directions for addiction research by highlighting the importance of communication between neurons and glia. Although nicotine dependence is widely recognized as a disorder of altered glutamate signaling, this study shows that astrocytes participate in the molecular processes that reinforce repeated nicotine use. While the work is preclinical, the implications for long-term research are significant.
“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 the development of therapeutic strategies that ultimately support smoking cessation efforts,” concludes Professor Choe.
Key questions answered:
A: Nicotine activates astrocyte receptors, triggering signaling pathways that increase glutamine synthetase activity and strengthen glutamate-driven reinforcing processes.
A: It shifts the focus from neurons solely to neuron-glia communication, revealing that astrocytes are active participants in the brain adaptations that maintain nicotine dependence.
A: While still preclinical, blocking astrocytic signaling reduced nicotine-induced sensitization in rats, suggesting that astrocytic pathways may be viable long-term therapeutic targets.
Editorial notes:
This article was edited by a Neuroscience News editor. Magazine article reviewed in its entirety. Additional context added by our staff.
About this news about nicotine addiction and neuroscience research
Author: Goon-Soo Kim
Source: Pusan National University
Contact: Goon-Soo Kim – Pusan National University
Image: Image is credited to Neuroscience News.
Original research: Open access.
“Glutamine synthetase in caudate and putamen astrocytes is responsible for locomotor sensitization after nicotine exposure” by Eun Sang Choe et al. Acta Pharmaceutica Sinica B
Abstract
Glutamine synthetase in caudate and putamen astrocytes is responsible for locomotor sensitization after nicotine exposure.
Glutamine synthetase (GS) in astrocytes regulates glutamatergic neurotransmission by maintaining glutamate clearance in the brain.
This study determined that GS in astrocytes of the caudate and putamen (CPu) regulates locomotor sensitization after repeated exposure to nicotine.
Nicotine increased phosphorylated c-Jun N-terminal kinase (pJNK) by stimulating α7 nicotinic acetylcholine receptors in cultured C6 glioma cells and primary astrocytes in a Ca2+-dependent manner.
Active JNK phosphorylated metabotropic glutamate receptor 1a (mGluR1a) at the carboxyl terminus of mGluR1a labeled with glutathione S-transferase in vitro. Interference with the pJNK-mGluR1a interaction using the inhibitory peptide, Tat-mGluR1a-i (10 μmol/L), diminished the nicotine-induced increase in GS activity in C6 glioma cells and primary astrocytes.
Similar results were obtained by bilateral intra-CPu infusion of the inhibitory peptide (2 nmol/side). Inhibition of GS activity by bilateral intra-CPu infusion of methionine sulfoximine (50 nmol/side) diminished the repeated nicotine-induced increase in locomotor activity.
These findings suggest that astrocytes in the CPu positively regulate locomotor sensitization by activating GS through the pJNK-mGluR1a interaction, which is linked to α7 nicotinic acetylcholine receptors in response to nicotine.
