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.

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.

Tobacco dependence is a chronic, relapsing disorder with significant socioeconomic and health impacts that lead to considerable morbidity and mortality worldwide. Nicotine is the primary component responsible for the initiation and continuation of tobacco use. Nicotine exposure causes multiple alterations in the structure and function of the brain's reward system. Evidence shows that synaptic plasticity, a key event that modifies neural circuit structure and function, is largely influenced by changes in glutamatergic neurotransmission in the forebrain's reward pathways. It is now widely accepted that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) modify synaptic strength within the reward circuitry. Dendritic spines, the primary sites of synaptic plasticity, exhibit an array of structural adaptations in size and shape influenced by neural activity, which correlates with alterations in the strength of synaptic connections. Such alterations in dendritic spine morphology largely depend on the remodeling of the underlying actin cytoskeleton. The dynamics of the actin cytoskeleton are regulated by several modulators, including actin-binding proteins, protein kinases, and small GTPases. This review focuses on the restructuring of the dendritic spine machinery and the relevant changes in synaptic strength mediated by AMPARs in key brain areas involved in addiction. However, our understanding of the neural pathways governing the emergence and significance of the structural and functional changes that lead to addiction-like behaviors after prolonged nicotine exposure remains insufficient. Comprehending these essential neural processes could deepen our insight into the progression and maintenance of nicotine dependence.

These findings suggest that active cofilin alters the structure of spine heads from mushroom to thin spine/filopodia by potentiating actin turnover, contributing to behavioral sensitization after nicotine exposure.

WCSC does not augment the nicotine-induced increases in behavioral sensitization, drug-taking behavior, and glutamate and dopamine concentrations, suggesting that non-nicotine substances do not potentiate the nicotine-induced behaviors by increasing the concentrations of the neurotransmitters in the CPu. These findings imply that nicotine, but not non-nicotine substances in WCSC, may be a major contributor that induces tobacco dependence in rats.

These findings suggest that the GluA1-Ser831 phosphorylation in the MSNs of the CPu is required for the challenge nicotine-induced behavioral sensitization in rats. CaMKII activation linked to mGluR5 and NMDA receptors, but not to D1R, is essential for inducing the CaMKII-Ser831 interaction.

Activation of protein kinases after cocaine administration controls psychomotor behaviours by interacting with metabotropic receptors in the brain. This study identified how c-Jun N-terminal kinase (JNK) interacts with metabotropic glutamate receptor 5 (mGluR5) in vitro and in the caudate and putamen (CPu). The potential role of this interaction in the regulation of psychomotor behaviour was also evaluated after administration of cocaine. Active JNK phosphorylates a threonine residue at position 1055 in the carboxyl terminus (CT) of mGluR5 in vitro. The binding of active JNK to the D-motif within CT2 is necessary for that phosphorylation. Interaction of phosphorylated JNK and mGluR5 occurs in the CPu. Unilateral interference of the interaction decreases the repeated cocaine-induced increases in locomotor activity and conditioned place preference. These findings suggest that activation of JNK has the capability to interact with mGluR5 in the CPu. Phosphorylation of mGluR5 following the JNK-mGluR5 interaction may be responsible for the potentiation of behavioural sensitisation and cocaine-wanting behaviour in response to cocaine administration.