The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.

Voluntary urination ensures that waste is eliminated when safe and socially appropriate, even without a pressing urge. Uncontrolled urination, or incontinence, is a common problem with few treatment options. Normal urine release requires a small region in the brainstem known as Barrington's nucleus (Bar), but specific neurons that relax the urethral sphincter and enable urine flow are unknown. Here we identify a small subset of Bar neurons that control the urethral sphincter in mice. These excitatory neurons express estrogen receptor 1 (Bar), project to sphincter-relaxing interneurons in the spinal cord and are active during natural urination. Optogenetic stimulation of Bar neurons rapidly initiates sphincter bursting and efficient voiding in anesthetized and behaving animals. Conversely, optogenetic and chemogenetic inhibition reveals their necessity in motivated urination behavior. The identification of these cells provides an expanded model for the control of urination and its dysfunction.

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Over the last decade oxycodone has become one of the most widely abused drugs. The emergence of oxycodone dependence as a serious health crisis has prompted a major need for animal models of oxycodone dependence with face and predictive validity. Oxycodone use in humans is more prevalent in women (Administration, 2014) and leads to pronounced hyperalgesia and irritability. However, it is unclear if the current animal model of oxycodone self-administration recapitulates these characteristics. We assessed the face validity of an extended access oxycodone self-administration model in rats by examining escalation of oxycodone intake and behavioral symptoms of withdrawal including irritability like behavior and mechanical nociception in male and female rats. We found that male and female rats escalated oxycodone intake over the course of 14 self-administration sessions, however, female rats escalated took more drug than male rats once escalated. When we assessed irritability-like behavior we found no differences between baseline or withdrawal, however when tested immediately after a 12-h self-administration session rats showed a decreased number of aggressive responses and a increased number of defensive responses. When tested for mechanical threshold during withdrawal rats showed pronounced hyperalgesia that was only partially reversed by oxycodone self-administration. The results of the present study demonstrate the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and demonstrating pronounced changes to pain and affective states.