bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/310334

Exploring sex differences in the prevention of ethanol drinking by naltrexone in dependent rats during abstinence

Matzeu, A.·Terenius, L.·Martin-Fardon, R.
View original source ↗Export metadata ↓

Abstract

BackgroundDespite considerable efforts, few drugs are available for the treatment of alcohol (ethanol [EtOH]) use disorders (AUDs). Ethanol directly or indirectly modulates several aspects of the central nervous system, including neurotransmitter/neuromodulator systems. Relapse vulnerability is a challenge for the treatment of EtOH addiction. Ethanol withdrawal symptoms create motivational states that lead to compulsive EtOH drinking and relapse even after long periods of abstinence. Among the therapeutics to treat AUDs, naltrexone (NTX) is a pharmacological treatment for relapse. The goal of the present study was to evaluate the effect of NTX on EtOH drinking in EtOH-dependent male and female rats during abstinence.\n\nMethodsWistar rats (males and females) were first trained to orally self-administer 10% EtOH. Half of them were then made dependent by chronic intermittent EtOH (CIE) vapor exposure, and the other half were exposed to air. Using this model, rats exhibit somatic and motivational signs of withdrawal. At the end of EtOH vapor (or air) exposure, the rats were tested for the effects of NTX (10 mg/kg, p.o.) on EtOH self-administration at three abstinence time points: acute abstinence (8 h, A-Abst), late abstinence (2 weeks, L-Abst), and protracted abstinence (6 weeks, P-Abst).\n\nResultsNTX decreased EtOH intake in nondependent rats, regardless of sex and abstinence time point. In post-dependent rats, the effects of NTX improved with a longer abstinence time (i.e., L-Abst and P-Abst) in males, whereas it similarly reduced EtOH drinking in females at all abstinence points.\n\nConclusionsThe data suggest that the therapeutic efficacy of NTX depends on the time of intervention during abstinence and sex. The data further suggest that EtOH dependence induces different neuroadaptations in male and female rats, reflected by differential effects of NTX. The results underscore the significance of considering the duration of EtOH abstinence and sex for the development of pharmacotherapeutic treatments for AUD.

Source connections

Explore related subjects

neurosciencePreprint

Keep this discovery

BibTeXRIS

Matzeu, A., Terenius, L., Martin-Fardon, R.. 2018-04-28. Exploring sex differences in the prevention of ethanol drinking by naltrexone in dependent rats during abstinence. https://doi.org/10.1101/310334

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗
bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗
bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗