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 nicotine exposure. Nicotine increased phosphorylated c-Jun N-terminal kinase (pJNK) by stimulating <i>α</i>7 nicotinic acetylcholine receptors in cultured glioma C6 cells and primary astrocytes in a Ca²⁺-dependent manner. Active JNK phosphorylated metabotropic glutamate receptor 1a (mGluR1a) at the carboxyl terminus of glutathione <i>S</i>-transferase-tagged mGluR1a <i>in vitro</i>. Interference with the pJNK-mGluR1a interaction using the inhibitory peptide, Tat-mGluR1a-i (10 μmol/L), decreased the nicotine-induced increase in GS activity in glioma C6 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) decreased the repeated nicotine-induced increase in locomotor activity. These findings suggest that astrocytes in the CPu upregulate locomotor sensitization by activating GS <i>via</i> the pJNK-mGluR1a interaction, which is linked to <i>α</i>7 nicotinic acetylcholine receptors in response to nicotine.

The major function of primary order neurons in the arcuate nucleus of the hypothalamus is control of energy homeostasis. Among these neurons, proopiomelanocortin (POMC) neurons play a significant role in controlling anorexigenic feeding behavior and upregulating energy expenditure. In addition, transient receptor potential melastatin 2 (TRPM2) is a well-established temperature sensor, but no evidence of regulation of brown adipose tissue (BAT) thermogenesis via POMC^TRPM2 neurons in the arcuate nucleus has been reported so far. Here, through single-cell reverse-transcription and immunohistochemistry analyses, we confirmed that a subset of POMC neurons express TRPM2. Also, we confirmed the neuronal connection between POMC and BAT using cholera toxin subunit B. The chemogenetic stimulation of POMC neurons induced BAT thermogenesis, and this thermogenic effect was inhibited by a TRPM2 blocker. These results indicate that TRPM2 could modulate POMC neuronal activity and play a role in regulating BAT activity through neuronal connections. Adenosine diphosphoribose (ADPR), a TRPM2 agonist, depolarized POMC neurons, and this effect was suppressed by TRP and TRPM2 antagonists. In addition, intracerebrovascular injection of ADPR increased c-Fos expression of a subset of POMC neurons, BAT and core body temperature and expression of IRF-4, but not uncoupling protein 1, in normal chow diet- and high-fat diet-fed mice. TRPM2 antagonists blocked this increase. Our findings offer new insights into the physiological mechanism of IRF-4-mediated BAT thermogenesis, which is regulated by acute activation of hypothalamic POMC^TRPM2 neurons. Consequently, these approaches to promoting BAT thermogenesis can provide novel basic concepts to establish therapeutic strategies and precautions to combat metabolic disorders.