Biology subjects

Vetreno, R. P.

Publications and source records attributed to Vetreno, R. P..

5 recordsLinked to original sources

bioRxiv2026

Chronic Intermittent Ethanol Exposure Produces Physiological Tolerance and Distinct Behavioral Alterations Across Abstinence in Female Mice

Chronic ethanol consumption produces long-lasting effects on the brain that contribute to persistent behavioral changes. This has been modeled in animals using the chronic intermittent ethanol (CIE) paradigm, which induces escalation of consumption and alterations in affective and cognitive behavior. While this model has been well characterized in male subjects, the effects of CIE in females and long-term effects that persist beyond the acute withdrawal remain relatively underexplored. Here, female C57BL/6J mice were exposed to four weeks of chronic intermittent ethanol (CIE) vapor to induce dependence. Following CIE, mice were evaluated for physiological tolerance to ethanol and alterations in anxiety-like behaviors and memory processing. Using the ethanol responsivity battery (ERB) assay to assess physiological tolerance, we found blunted responsiveness to the intoxicating effects of ethanol in the CIE-exposed females, indicating heightened ethanol tolerance that persists beyond the acute withdrawal phase. A cohort underwent behavioral testing following CIE to characterize changes in anxiety-like behavior, exploration, and memory across abstinence. In early abstinence (<5 days post-CIE), CIE-exposed females showed increased exploratory behavior compared with Air controls. After one week of abstinence, CIE-exposed females displayed impaired object recognition memory. CIE-exposed females also showed increased anxiety-like behavior at protracted abstinence time points, exhibiting hyponeophagia in the novelty-suppressed feeding test at 2 weeks post-CIE. In addition, following cued fear conditioning, we found reduced extinction recall at 4 weeks post-CIE. Together, this work indicates that chronic alcohol exposure leads to increased alcohol tolerance and distinct, persistent alterations in memory and anxiety-like behavior in female mice.

neuroscience↗

bioRxiv2024

β-arrestin-biased Allosteric Modulator of Neurotensin Receptor 1 Reduces Ethanol Drinking and Responses to Ethanol Administration in Rodents

Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death1. Despite this, there are currently only 3 FDA approved pharmacological treatments for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant misuse. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces binge-like ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

neuroscience↗

bioRxiv2022

Impact of adolescent intermittent ethanol exposure on interneurons and their surrounding perineuronal nets in adulthood.

BackgroundBinge alcohol exposure during adolescence results in long-lasting alterations in brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long-term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony, and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) surround some interneurons, particularly PV+ interneurons, to further regulate cellular plasticity. The effect of AIE exposure on expression of these markers within the PFC is not well understood. MethodsThe present study tested the hypothesis that AIE exposure reduces expression of PV+ and ChAT+ interneurons in the adult PFC and striatum and increases related expression of PNNs (marked by binding of Wisteria Floribunda agglutinin lectin; WFA) in adulthood. Male rats were exposed to AIE (5 g/kg/day, 2-days-on/2-days-off, i.g., P25-P54) or water (CON), and brain tissue was harvested in adulthood (> P80). Immunohistochemistry and co-immunofluorescence were used to assess expression of ChAT, PV, and WFA labeling within the adult PFC and striatum following AIE exposure. ResultsChAT and PV interneuron numbers in the striatum and PFC were unchanged after AIE exposure. However, WFA labeling in the PFC of AIE-exposed rats was increased compared to CON rats. Moreover, significantly more PV neurons were surrounded by WFA labeling in AIE-exposed subjects relative to controls in both PFC subregions assessed: the orbitofrontal cortex (CON = 34%; AIE = 40%) and the medial PFC (CON = 10%; AIE = 14%). ConclusionsThese findings indicate that while PV interneuron expression in the adult PFC and striatum is unaltered following AIE exposure, PNNs surrounding these neurons (indicated by extracellular WFA binding) are increased. This increase in PNNs may restrict plasticity of the ensheathed neurons, thus contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.

neuroscience↗

bioRxiv2021

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats

Toll-like receptor (TLR) signaling may play an important role in the neuroimmune systems involvement in the development and maintenance of alcohol use disorder. In the present study we administered TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption in a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg, however when instead 1.0 mg/kg was given on consecutive days alcohol intake increased in the days following injections specifically in females. Furthermore, in a second experiment we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final experiment the dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions on injection days in females that were not accompanied by subsequent increases. The dose was increased to 9 mg/kg for one final pair of injections which led to reductions in intake in both males and females but only increased subsequent alcohol consumption in males. Overall, poly(I:C) was able to increase subsequent alcohol consumption in both sexes, with females being sensitive to lower doses than males both in terms of changes in alcohol consumption and general locomotor reduction. These findings show that TLR3 agonism may be involved in driving increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.

neuroscience↗

bioRxiv2021

The toll-like receptor 7 agonist imiquimod increases ethanol self-administration and induces expression of toll-like receptor related genes

BackgroundThere is growing evidence that immune signaling may be involved in both the causes and consequences of alcohol abuse. Toll-like receptor (TLR) expression is increased by alcohol consumption and is implicated in AUD, and specifically TLR7 may play an important role in ethanol consumption. MethodsWe administered the TLR7-specific agonist imiquimod in male and female Long-Evans rats to determine 1) gene expression changes in brain regions involved in alcohol reinforcement, the nucleus accumbens core and anterior insular cortex, in rats with and without an alcohol history, and 2) whether TLR7 activation could modulate operant alcohol self-administration. ResultsInterferon regulatory factor 7 (IRF7) was dramatically increased in both sexes at both 2 and 24 h post-injection regardless of alcohol history, while TLR3 and 7 gene expression changes were region- and sex-specific. The pro-inflammatory cytokine TNF was increased 24h post-injection in rats with an alcohol self-administration history but this effect did not persist after four injections, suggesting molecular tolerance. In both males and females, ethanol consumption was increased 24 h after imiquimod injections with sex-specific differences: in females this effect emerged following the first injection but in males this increase did not occur until the third injection, suggesting sex differences in adaptation to repeated TLR7 activation. Notably, imiquimod reliably induced weight loss, indicating that sickness behavior persisted across repeated injections. ConclusionThese findings show that TLR7 activation can modulate alcohol drinking in an operant self-administration paradigm, and suggest that TLR7 and IRF7 signaling pathways may be a viable druggable target for treatment of AUD.

neuroscience↗