Title: Astrocytes drive nicotine-induced brain changes by boosting glutamate cycling — a shift from the neuron-centered view of addiction

New research from Pusan National University shows astrocytes actively shape nicotine-induced neural adaptations that underlie addictive behavior. The study finds that nicotine stimulates receptors on astrocytes, triggering calcium-dependent signaling that increases glutamine synthetase (GS) activity and amplifies glutamate–glutamine cycling. Those molecular changes strengthen locomotor sensitization — a hallmark of addiction-like brain plasticity — and blocking a key astrocytic interaction reduced these behavioral effects in rats, pointing to new directions for addiction research.

Key findings
– Astrocyte activation: Nicotine stimulates α7 nicotinic acetylcholine receptors on astrocytes in the caudate–putamen (CPu), producing a Ca2+ rise that activates phosphorylated c-Jun N-terminal kinase (pJNK).
– Signaling cascade: Activated pJNK interacts with metabotropic glutamate receptor 1a (mGluR1a), increasing GS activity in astrocytes.
– Glutamate pathway: Elevated GS activity enhances the glutamate–glutamine cycle, reinforcing glutamate-driven neural adaptations linked to addiction.
– Therapeutic potential: Disrupting the pJNK–mGluR1a interaction with a designed inhibitory peptide (Tat-mGluR1a-i) or inhibiting GS reduced nicotine-induced increases in GS activity and dampened locomotor sensitization in rats.

Background and significance
Nicotine addiction is sustained by brain changes that reinforce repeated use and make quitting difficult. Historically, research has focused on neurons, but growing evidence points to active roles for glial cells. Professor Eun Sang Choe’s team investigated how astrocytes contribute to nicotine-induced brain changes, centering on glutamine synthetase, the enzyme that helps regulate glutamate — the brain’s chief excitatory neurotransmitter.

Study outline and results
– The study was published online in Acta Pharmaceutica Sinica B on 25 September 2025.
– Repeated nicotine injections in rat models activated α7 nicotinic receptors on astrocytes in the CPu, triggering intracellular Ca2+ increases.
– The Ca2+ rise led to pJNK activation. In vitro, active JNK phosphorylated mGluR1a at its carboxyl terminus (shown with glutathione S‑transferase-tagged mGluR1a).
– The pJNK–mGluR1a interaction increased GS activity, driving up glutamate–glutamine cycling and producing enhanced locomotor sensitization.
– Interfering with the pJNK–mGluR1a interaction using the inhibitory peptide Tat‑mGluR1a‑i (10 μmol/L in cell models; 2 nmol/side for bilateral intra‑CPu infusion) decreased nicotine‑induced GS activity in glioma C6 cells, primary astrocytes, and in vivo.
– Direct inhibition of GS in the CPu with methionine sulfoximine (50 nmol/side) also reduced the repeated nicotine‑induced increase in locomotor activity.

Interpretation and implications
These results show that astrocytes in the CPu actively contribute to the neural adaptations produced by repeated nicotine exposure via a Ca2+ → pJNK → mGluR1a → GS pathway. By highlighting neuron–glia communication as a driver of nicotine‑related plasticity, the work broadens the target landscape for addiction research. Although the findings are preclinical and clinical translation will take time, they suggest astrocytic signaling pathways could become long‑term targets for interventions to support smoking cessation.

Comment from the lead author
“Most studies on nicotine addiction have focused on neurons and overlooked glial cells. Our study demonstrates that astrocytes interact with neurons in the brain’s reward system to regulate nicotine‑dependent behavior, advancing the current understanding of nicotine addiction,” says Prof. Choe.

Key questions answered
Q: How do astrocytes contribute to nicotine addiction?
A: Nicotine activates α7 receptors on astrocytes, producing Ca2+-dependent pJNK activation that engages mGluR1a and increases GS activity, strengthening glutamate-driven reinforcement processes.

Q: Why is this study important for addiction research?
A: It shifts attention from neurons alone to neuron–glia communication, revealing astrocytes as active participants in the brain adaptations that sustain nicotine dependence.

Q: Could targeting astrocytes help develop new smoking‑cessation treatments?
A: In this preclinical work, blocking astrocytic signaling reduced nicotine‑induced sensitization in rats, suggesting astrocytic pathways may be viable long‑term therapeutic targets.

Study and publication details
– Source: Pusan National University
– Author of article: Goon‑Soo Kim (Pusan National University contact: Goon‑Soo Kim)
– Journal: Acta Pharmaceutica Sinica B (published online 25 September 2025)
– Research article: “Glutamine synthetase in astrocytes of the caudate and putamen is responsible for locomotor sensitization after nicotine exposure” by Eun Sang Choe et al. (open access)

Abstract summary
The study demonstrates that GS in CPu astrocytes regulates locomotor sensitization after repeated nicotine exposure. Nicotine increased pJNK via α7 receptors in a Ca2+-dependent manner in cultured glioma C6 cells and primary astrocytes. Active JNK phosphorylated mGluR1a in vitro, and disrupting the pJNK–mGluR1a interaction with Tat‑mGluR1a‑i reduced nicotine‑induced GS activity. Bilateral intra‑CPu infusion of the inhibitory peptide produced similar effects in vivo, and inhibiting GS with methionine sulfoximine lowered nicotine‑induced locomotor activity. These findings indicate that astrocytic GS upregulation via the pJNK–mGluR1a interaction, linked to α7 nicotinic receptors, contributes to nicotine‑induced locomotor sensitization.

This article was adapted from an original report published on neurosciencenews.com. All rights belong to the original publisher.