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Results for “GABAergic System”

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6 recordsLinked to original sources

PubMed2025

Genetic and Epigenetic Approaches to Opioid Use Disorder.

BACKGROUND: Opioid use disorder (OUD) is a major global-scale social issue affecting public health. The high potential for addiction and dependence makes opioid use a significant concern, contributing to substance-related disorders. Both genetic and environmental factors contribute to the predisposition to OUD, with the opioidergic, dopaminergic, and GABAergic systems playing primary roles in itsonset. METHODS: This narrative review documents the association between genes and their variants related to these three systems, along with current evidence on epigenetic interventions in OUD. Relevant studies investigating candidate-gene associations and molecular mechanisms were synthesized to highlight genetic variants and epigenetic processes linked to OUD. RESULTS: Genetic associations play a prominent role in OUD, with several single-nucleotide variants identified in affected populations. Key genes implicated include OPRM1, OPRD1, OPRK1, PDYN, OPRL1, and POMC from the opioidergic system; DRD1, DRD2, DRD3, DRD4, ANKK1, and COMT from the dopaminergic system; and GABRA2, GABRB3, GABRG2, GAD1, and GAD2 from the GABAergic system. Evidence also indicates that chronic opioid use is associated with epigenetic changes through posttranslational histone modifications and DNA methylation. However, limitations in existing studies include small sample sizes, limited replication, and potential stratification biases. CONCLUSIONS: Although many candidate-gene associations have been proposed for OUD, robust evidence remains limited. Large, ancestrally diverse genome-wide association studies (GWAS) and systematic replication studies are urgently needed. A deeper understanding of the genetic, epigenetic, and neurobiological bases of addiction will be essential for the development of precisely targeted medications to improve prevention and treatment outcomes for OUD.

Humans↗

PubMed2026

Prevention of postpartum methamphetamine use with micronized progesterone trial (PROMPT): A pilot randomized controlled trial.

OBJECTIVES: Methamphetamine use disorder (MUD) contributes to postpartum morbidity and mortality. Postpartum progesterone decline may destabilize γ-aminobutyric acid pathways, increasing craving and return to use. We assessed the feasibility and safety of micronized progesterone, generating efficacy estimates for preventing postpartum methamphetamine use. METHODS: We conducted a double-blind, randomized, placebo-controlled feasibility trial (November 2021-January 2024) at an academic center with a perinatal addiction clinic. Participants ≤ 12 weeks postpartum with ≥ 4 weeks of abstinence were randomized 1:1, stratified by opioid use disorder (OUD), to micronized progesterone 400mg (200mg twice daily) or identical placebo for 12 weeks. The primary outcome was feasibility, defined as achieving ≥ 80% of planned enrollment. Safety outcomes included adverse events (AEs) and serious adverse events (SAEs). Efficacy outcomes were return to methamphetamine use (weekly self-report and every two weeks urine toxicology) and methamphetamine craving. Analyses included intent-to-treat and per-protocol approaches, with loss to follow-up imputed as return to use. Craving trajectories were modeled using adjusted regression with interaction terms for medication for OUD (MOUD). RESULTS: Of 253 screened individuals, 43 were eligible and 34 were enrolled (91.8%; 18 progesterone, 16 placebo). Retention at 12 weeks was 88%. AE frequency was similar between groups (78% vs 81%; p > 0.05), and no maternal SAEs occurred. Four infant SAEs were deemed unrelated to treatment. Return to methamphetamine use did not differ between groups. Craving trajectories differed by MOUD type. CONCLUSIONS: Micronized progesterone was feasible and safe for postpartum individuals with MUD. MOUD-specific craving effects support evaluation in larger, multicenter efficacy trials. GOV REGISTRATION NUMBER: NCT05128071 NCT REGISTRATION: Prevention of postpartum methamphetamine use with micronized progesterone trial https://clinicaltrials.gov/study/NCT05128071.

Humans↗

PubMed2025

RNA-RNA interactions coordinate GABA metabolism and signaling.

Production, signaling, and degradation of the inhibitory neurotransmitter GABA requires tight regulation for proper nervous system function, yet the gene regulatory mechanisms underlying this control remain poorly understood. Here, we identify a post-transcriptional mechanism that coordinates expression of the GABA synthetase Gad1 with its vesicular transporter VGAT in Drosophila. While Gad1 is transcribed specifically in GABAergic neurons, VGAT mRNA is transcribed broadly across the nervous system, but is selectively translated in GABAergic neurons. We show that this specificity depends on CG14989, a putative long non-coding RNA located adjacent to the Gad1 gene locus that shares its GABAergic expression pattern. CG14989 RNA contains sequences complementary to three predicted miR-7 sites in the VGAT 3'UTR, and ectopic expression experiments revealed that it is sufficient for VGAT translation in non-GABAergic neurons, consistent with antagonism of miR-7-mediated repression. Furthermore, complementary regions to CG14989 are present in multiple other genes related to metabolism and signaling of GABA, suggesting a broader role for this mechanism. Together, our findings suggest that CG14989 functions as a regulatory hub that coordinates the molecular identity of GABAergic neurons.

Journal Article↗

PubMed2025

Impacts of hnRNP A1 Splicing Inhibition on the Brain Remyelination Proteome.

Oligodendrocytes, the myelinating cells in the central nervous system, are implicated in several neurological disorders marked by dysfunctional RNA-binding proteins (RBPs). The present study aimed at investigating the role of hnRNP A1 in the proteome of the corpus callosum, prefrontal cortex, and hippocampus of a murine cuprizone-induced demyelination model. Right after the cuprizone insult, we administered an hnRNP A1 splicing activity inhibitor and analyzed its impact on brain remyelination by nanoESI-LC-MS/MS label-free proteomic analysis to assess the biological processes affected in these brain regions. Significant alterations in essential myelination proteins highlighted the involvement of hnRNP A1 in maintaining myelin integrity. Pathways related to sphingolipid and endocannabinoid signaling were affected, as well as the synaptic vesicle cycle and GABAergic synapses. Although behavioral impairments were not observed, molecular changes suggest potential links to memory, synaptic function, and neurotransmission processes. These findings enhance our understanding of the multifaceted roles of hnRNP A1 in the central nervous system, providing valuable insights for future investigations and therapeutic interventions in neurodegenerative and demyelinating diseases.

Animals↗

PubMed2026

Characterization of age-related changes in the gut microbiome and metabolome of Kunming dogs and their associations with police performance.

BACKGROUND: Gut microbiota plays a pivotal role in regulating the host's central nervous system (CNS) activity and behavior. However, its influence on the police performance of Kunming dogs and the underlying mechanisms remain largely unexplored. This study was the first to apply multi-omics technologies to investigate the dynamic variations in gut microbiota and their metabolic profiles across different ages of Kunming dogs. Furthermore, we systematically examined the associations between these microbial alterations and police performance metrics, providing a theoretical foundation for enhancing the working capabilities of Kunming dogs through targeted modulation of intestinal microecology. RESULTS: The study showed that puppies, young dogs and adult dogs had significantly better police performance than elderly dogs, with young dogs exhibiting the highest scores. Analysis of 16S rRNA sequencing demonstrated that gut microbial diversity and stability were highest during the young dog stage, gradually declining with age. Metagenomic analysis revealed that the abundance of Lactobacillus acidophilus, Lactobacillus johnsonii, Limosilactobacillus reuteri, Ligilactobacillus animalis and Muribaculum gordoncarteri were strongly correlated with police performance. The results of metagenome-assembled genomes (MAGs) indicated that the above species have functional genes involved in GABAergic and glutamatergic synapse pathways. Furthermore, metabolomic analysis showed that differential metabolites were enriched in the neuroactive ligand-receptor interaction pathway, in which GABA (γ-aminobutyric acid), histamine and tyramine metabolites were positively correlated with the above species and police performance. CONCLUSION: The species L. acidophilus, L. johnsonii, L. reuteri, L. animalis, and M. gordoncarteri, which were enriched in the gut of puppies and young Kunming dogs, may potentially influence the nervous system through the production of neurotransmitters and neuromodulators, suggesting a possible association with police performance. Video Abstract.

Animals↗

PubMed2025

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy.

PURPOSE: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease. METHODS: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system. RESULTS: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling. CONCLUSION: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Humans↗