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Opioid Use Disorder (OUD) is a chronic and relapsing psychiatric condition which is currently the leading cause of accidental death in the US. Symptoms of acute opioid withdrawal resemble a flu-like illness which is accompanied by a dysphoric state. Psychological comorbidities such as anxiety, depression, and disordered sleep can persist for months or years, well into the abstinence period. These symptoms are thought to drive further opioid intake in order to alleviate this unpleasant internal state. Many differences in OUD have been documented between male and female patients, with females at higher risk for relapse and overdose. This study sets out to characterize sex differences in symptoms and behavioral adaptations in mice during early withdrawal. Using our moderate dose, three day precipitated withdrawal paradigm, we discovered significant effects of sex, time, and drug treatment on early withdrawal behaviors, locomotor activity, and gut motility in C57BL/6J mice. Here I will discuss previous methods of condensing behavioral phenotypes into one global withdrawal score, and propose a new methodology. This method increases the ability to detect nuanced effects and allows for more accurate translation across strain, sex, paradigm, and experimental context. Classification of opioid withdrawal-induced behavioral adaptations will allow for improved behavioral analysis of pharmacological manipulations, and investigations of brain circuitry involved in opioid withdrawal, as well as future screening of compounds with potential therapeutic benefit for the treatment of OUD.

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Despite strong preclinical evidence for the ability of corticotropin releasing factor 1 (CRF1) antagonists to regulate alcohol consumption, clinical trials have not yet demonstrated therapeutic effects of these compounds in alcohol use disorder (AUD) patients. Several confounding factors may limit the translation of preclinical CRF1 research to patients, including reliance on experimenter‐administered alcohol instead of voluntary consumption, a preponderance of evidence collected in male subjects only and an inability to assess the effects of alcohol on specific brain circuits. A population of particular interest is the CRF1‐containing neurons of the central amygdala (CeA). CRF1 CeA neurons are sensitive to ethanol, but the effects of alcohol drinking on CRF signalling within this population are unknown. In the present study, we assessed the effects of voluntary alcohol drinking on inhibitory control of CRF1+ CeA neurons from male and female CRF1:GFP mice using ex vivo electrophysiology and determined the contributions of CRF1 signalling to inhibitory control and voluntary alcohol drinking. Chronic alcohol drinking produced neuroadaptations in CRF1+ neurons that increased the sensitivity of GABAA receptor‐mediated sIPSCs to the acute effects of alcohol, CRF and the CRF1 antagonist R121919, but these adaptations were more pronounced in male versus female mice. The CRF1 antagonist CP‐154,526 reduced voluntary alcohol drinking in both sexes and abolished sex differences in alcohol drinking. The lack of alcohol‐induced adaptation in the female CRF1 system may be related to the elevated alcohol intake exhibited by female mice and could contribute to the ineffectiveness of CRF1 antagonists in female AUD patients.

Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. In addition to homeostatic feeding mechanisms, there is growing recognition of the involvement of food reward and motivation in the development of obesity. However, it remains unclear how brain circuits that control food reward and motivation are altered in obese animals. Here, we tested the hypothesis that signaling through pro-motivational circuits in the core of the nucleus accumbens (NAc) is enhanced in the obese state, leading to invigoration of food seeking. Using a novel behavioral assay that quantifies physical work during food seeking, we confirmed that obese mice work harder than lean mice to obtain food, consistent with an increase in the relative reinforcing value of food in the obese state. To explain this behavioral finding, we recorded neural activity in the NAc core with both in vivo electrophysiology and cell-type specific calcium fiber photometry. Here we observed greater activation of D1-receptor expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. With ex vivo slice physiology we identified both pre- and post-synaptic mechanisms that contribute to this enhancement in NAc D1SPN activity in obese mice. Finally, blocking synaptic transmission from D1SPNs decreased physical work during food seeking and attenuated high-fat diet-induced weight gain. These experiments demonstrate that obesity is associated with a selective increase in the activity of D1SPNs during food seeking, which enhances the vigor of food seeking. This work also establishes the necessity of D1SPNs in the development of diet-induced obesity, identifying a novel potential therapeutic target.

Post-traumatic stress disorder (PTSD) confers enhanced vulnerability to develop comorbid alcohol use disorder (AUD). Exposure to the scent of a predator, such as the fox odor TMT, has been used to model a traumatic stressor with relevance to PTSD symptomatology. Alcohol produces distinct interoceptive (subjective) effects that may influence vulnerability to problem drinking and AUD. As such, understanding the lasting impact of stressor on sensitivity to the interoceptive effects of alcohol is clinically relevant. The present study used a 2-lever, operant drug discrimination procedure to train male, Long-Evans rats to discriminate the interoceptive effects of alcohol (2 g/kg, IG) from water. Upon stable performance, rats underwent a 15-min exposure to TMT. Two weeks later, an alcohol dose-response curve was conducted to evaluate the lasting effects of the TMT stressor on the interoceptive effects of alcohol. The TMT group showed a leftward shift in ED50 of the dose response curve compared to controls, reflecting potentiated interoceptive sensitivity to alcohol. TMT exposure did not affect response rate. GABAergic signaling in both the anterior insular cortex (aIC) and the nucleus accumbens (Acb) is involved in the interoceptive effects of alcohol and stressor-induced adaptations. As such, follow-up experiments in alcohol-naive rats examined neuronal activation (as measured by c-Fos immunoreactivity) following TMT and showed that TMT exposure increased c-Fos expression in the aIC and the nucleus accumbens core (AcbC). 2 weeks after TMT exposure, Gad-1 gene expression was elevated in the aIC and Gat-1 was increased in the Acb compared to controls. Lastly, the alcohol discrimination and alcohol-naive groups displayed dramatic differences in stress reactive behaviors during the TMT exposure, suggesting that alcohol exposure may alter the behavioral response to predator odor. Together, these data suggest that predator odor stressor results in potentiated sensitivity to alcohol possibly through GABAergic adaptations in the aIC and Acb, which may be relevant to understanding PTSD-AUD comorbidity.

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