Biology subjects

Carew, J. M.

Publications and source records attributed to Carew, J. M..

3 recordsLinked to original sources

bioRxiv2026

INTERFERON-REGULATORY FACTOR 7: A NEUROIMMUNE ROLE FOR VAPOR-INDUCED ESCALATIONS IN ETHANOL SELF-ADMINISTRATION

Neuroimmune signaling is increased in postmortem brain tissue from individuals with alcohol use disorder (AUD), and growing evidence suggests that it contributes to persistent alcohol-related neuroadaptations. Interferon regulatory factor 7 (IRF7), a transcription factor downstream of endosomal Toll-like receptor signaling, is induced in alcohol-relevant brain regions and may contribute to escalated drinking. Here, we tested whether chronic intermittent ethanol (CIE) vapor exposure engages IRF7 signaling during subsequent alcohol self-administration and whether this is associated with altered molecular E/I balance in the aIC and altered functional E/I balance in aICnucleus accumbens projection neurons. Female Wistar rats (n=30) were trained to self-administer alcohol (15% v/v; FR2 vs inactive lever) during 30-minute sessions. After establishing baseline drinking, rats underwent 1-3 cycles of CIE, which increased alcohol self-administration at the 72 h post vapor test. This increase positively correlated with IRF7 levels in the anterior insular cortex (aIC) and nucleus accumbens, while molecular, and immunofluorescence showed that CIE shifted aIC excitatory/inhibitory (E/I) balance toward reduced excitation. Electrophysiological recordings further showed reduced functional E/I balance in aIC neurons projecting to the nucleus accumbens. Knockdown of IRF7 in the aIC attenuated CIE induced escalation of alcohol self-administration, supporting a role for insular IRF7 signaling in alcohol related neuroadaptations that promote escalated drinking.

neuroscience↗

bioRxiv2025

Semaglutide, Tirzepatide, and Retatrutide Attenuate the Interoceptive Effects of Alcohol in Male and Female Rats

RationaleAlcohol use disorder (AUD) remains a major public health challenge, yet effective pharmacotherapies are limited. As such, there is growing interest in repurposing medications with novel mechanisms of action. Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for type 2 diabetes, have emerged as promising candidates due to effects on intake regulation and reward processing. GLP-1 receptor agonists, including semaglutide, reduce alcohol intake and relapse-like behaviors in rodent and non-human primate models, and a recent clinical trial found that semaglutide decreased alcohol craving and drinking in adults with AUD. Modulation of the subjective/interoceptive effects of alcohol may contribute to the therapeutic potential of GLP-1 receptor agonists. ObjectivesThis study used operant drug discrimination in male and female rats to assess how acute and repeated semaglutide treatment affects alcohols discriminative stimulus (interoceptive) effects. We hypothesized that GLP-1 receptor activation would disrupt alcohols interoceptive effects. We also evaluated acute treatment with tirzepatide, a dual GLP-1/gastric inhibitory peptide (GIP) receptor agonist, and retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, to determine whether broader receptor activity would differentially influence alcohols subjective effects. ResultsAcute administration of semaglutide, tirzepatide, and retatrutide each attenuated alcohol discrimination, suggesting modulation of subjective alcohol effects. Repeated semaglutide maintained efficacy across the 15-day treatment period; alcohol discrimination returned to control levels three days after treatment cessation. ConclusionsBuilding on prior work with GLP-1 receptor agonists, these results provide important context for interpreting clinical observations of reduced drinking behavior among individuals receiving this class of therapeutics.

neuroscience↗

bioRxiv2025

Xylazine potentiates the interoceptive effects of fentanyl in male and female rats

RationaleXylazine, a sedative typically used in veterinary medicine, has been increasingly detected as an adulterant in the unregulated opioid supply and present in opioid overdose deaths. Therefore, xylazine-adulterated fentanyl is a growing public health concern. People who use drugs have reported that xylazine changes and prolongs the effects of fentanyl ObjectivesWe used standard operant drug discrimination procedures to better understand how xylazine impacts the discriminative stimulus/interoceptive effects of fentanyl. MethodsMale and female Long-Evans rats (n=23) were trained to discriminate fentanyl (0.032 mg/kg intraperitoneal) such that one lever was reinforced with sucrose on days when fentanyl was administered, and the other lever was reinforced when vehicle was administered. Once rats met testing criteria, we tested a dose range of fentanyl to confirm discriminative stimulus control, then we tested if xylazine alone produced fentanyl-like effects and if the addition of xylazine to fentanyl impacted fentanyl interoceptive effects. ResultsStimulus control was confirmed, as rats showed increased percent responses on the fentanyl-appropriate lever as well as decreased response rates for increasing doses of fentanyl. Xylazine alone did not substitute for the stimulus effects of fentanyl but produced similar response rate reductions as fentanyl alone. Xylazine co-administered with fentanyl potentiated the stimulus effects of lower doses of fentanyl in both males and females and potentiated response rate reductions. ConclusionsThese results indicate that xylazine enhances the interoceptive effects of fentanyl, which may inform clinical research about xylazine-adulterated fentanyl.

neuroscience↗