Aug 2026· Acta Pharmacologica Sinica· 0 citations· 66 references
Medicine
TL;DR
It is demonstrated that S1R is involved in METH-induced behavioral sensitization and that SOMCL-668 could be a potential therapeutic agent for drug addiction.
Summary Abnormal excitatory synaptic function plays a critical role in major depressive disorder. In this study, we investigated the role of the A3 adenosine receptor (A3AR), previously implicated in affective disorders, in excitatory synapse formation within prefrontal cortical circuits. Using a corticosterone-induced mouse model of depression, we found that the adenosine receptor activator 3′-deoxyadenosine (3′dA) produced antidepressant-like effects and selectively increased A3AR expression, whereas fluoxetine did not. 3′dA also restored the synaptic organizers neuroligin-2 (NLGN2) and neurexin-2 and elevated BDNF, excitatory synaptic markers (synapsin-1, PSD-95, and GluR1), and dendritic spine density in the PFC. Notably, enhanced NLGN2 immunoreactivity co-localized with astrocytes exclusively in 3′dA-treated mice but not in fluoxetine-treated mice. Pharmacological blockade of A3AR with MRS-1191 prevented the 3′dA-induced behavioral and molecular changes in this corticosterone-induced depressive-like mouse model. Together, our findings identify A3AR as a key regulator of NLGN2 expression and excitatory synapse formation and suggest a potential target for antidepressant therapies.
Bai Li, Meng Zeng, Jiahui Liu et al.· iScience· 0 citations
By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression by restoring neurotrophic signaling and dopaminergic function in the nucleus accumbens.
Kuan-Yin Tseng, Tung-Tai Kuo, Pi-Kai Chang et al.· Journal of Parkinson's Disea...· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
Current research into the actions of psychedelic drugs is focused on 5-HT2A receptor-coupled signaling pathways, particularly β-arrestin2 signaling. Here, we investigated the involvement of β-arrestin2 in psychedelic drug-induced mouse markers of hallucinogenic effects, molecular plasticity, and structural plasticity; specifically, the head-twitch response, cortical expression of plasticity-related genes (cFos, Egr1, Egr2, and Arc), and dendritogenesis (primary cortical neuron cultures), respectively. Psilocin-induced head-twitches, plasticity gene expression, and dendritogenesis were all blocked by the 5-HT2A receptor antagonist MDL-100,907. The head-twitch response to psilocin was not different between wildtype and β-arrestin2 knockout (KO) mice, and the head-twitch responses to 2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) were similarly unaffected by β-arrestin2 KO. Psilocin-evoked gene expression showed a trend to be less in β-arrestin2 KO compared to wildtype mice, but the gene expression response to DOI was clearly not altered by β-arrestin2 KO. Finally, psilocin-induced dendritogenesis was attenuated in β-arrestin2 KO versus wild-type cultured neurons, and similar findings were obtained with DOI. In summary, the current study found no convincing evidence to support a role for β-arrestin2 signaling in either the head-twitch or plasticity-related gene responses to the psychedelic drugs tested. However, our data suggest a role for the β-arrestin2 pathway in psychedelic drug-evoked dendritogenesis of cultured neurons. Thus, the β-arrestin2 pathway unlikely mediates the hallucinogenic effects of psychedelic drugs but may contribute to neural plasticity changes in certain models.
Aurelija Ippolito, Agnese Tiranti, Shaun Hurley et al.· ACS Chemical Neuroscience· 0 citations
BACKGROUND AND PURPOSE
Microglia are central regulators of neuroinflammation in depression. Drivers involved remain incompletely understood. Sigma non-opioid intracellular receptor 1 (S1R) is involved in brain inflammation. This study investigates how S1R regulates neuroinflammation associated with depression.
EXPERIMENTAL APPROACH
Using integrated machine learning and single-cell transcriptomics, a key gene implicated in microglial dysfunction in depression was identified. Its relevance was examined in a lipopolysaccharide (LPS)-induced mouse model of depression and LPS-stimulated BV-2 cells. Further, targeted knockdown or overexpression of this gene was performed on medial prefrontal cortex (mPFC) microglia, followed by integrated behavioural, cellular and molecular analyses.
KEY RESULTS
Plxdc2 was the key gene up-regulated at both transcriptional and protein levels in blood and depression-susceptible brain regions. Single-cell RNA sequencing confirmed its specific enrichment in microglia, particularly within inflammatory gene sets related to N-linked glycosylation (NLG). LPS-treated mice, depressive-like behaviours were accompanied by elevated expression of Plxdc2 and the glycosylation-related enzyme β-1,4-galactosyltransferase 1 in mPFC microglia. The S1R agonist Hypidone hydrochloride (YL-0919) or conditional knockdown of Plxdc2, reversed these molecular changes, reduced neuroinflammation and alleviated depressive-like behaviours. Analysis demonstrated that overexpressing Plxdc2 in mPFC microglia activated the JAK2-STAT1 pathway, enhanced NLG, shifting microglia towards a pro-inflammatory phenotype, worsening deficits in synaptic plasticity and induced depressive-like behaviour. These were reversible by the NLG inhibitor tunicamycin.
CONCLUSIONS AND IMPLICATIONS
Plxdc2 promotes depressive-like behaviours by dysregulating NLG-mediated inflammatory in microglia. S1R activation has a therapeutic effect by inhibiting this pathway, positioning the S1R-Plxdc2 axis as a potential target for modulating microglial function in inflammation-related depression.
Jing-ya Wang, Peng Ren, De-yi Yang et al.· British Journal of Pharmacol...· 0 citations
Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.
Shanglan Qu, Xin Peng, Jieyu Ji et al.· Frontiers in Pharmacology· 0 citations
