Acknowledgements: Cocaine HCl used in these studies was generously obtained through the NIDA Drug Supply Program. The authors thank Dr. Debra Bangasser at Temple University for her guidance and input on estrous cycle monitoring.

Cocaine addiction is a chronic, relapsing disorder. Stress and cues related to cocaine are two common relapse triggers. We have recently shown that exposure to repeated restraint stress during early withdrawal accelerates the time-dependent intensification or "incubation" of cue-induced cocaine craving that occurs during the first month of withdrawal, although craving ultimately plateaus at the same level observed in controls. These data indicate that chronic stress exposure during early withdrawal may result in increased vulnerability to cue-induced relapse during this period. Previous studies have shown that chronic stress exposure in drug-naïve rats increases neuronal activity in the basolateral amygdala (BLA), a region critical for behavioral responses to stress. Given that glutamatergic projections from the BLA to the nucleus accumbens are critical for the incubation of cue-induced cocaine craving, we hypothesized that cocaine withdrawal and chronic stress exposure produce separate increases that additively increase BLA neuronal activity. To assess this, we conducted in vivo extracellular single-unit recordings from the BLA of anesthetized adult male rats following cocaine or saline self-administration (6 h/day for 10 days) and repeated restraint stress or control conditions on withdrawal days (WD) 6-14. Recordings were conducted from WD15 to WD20. Interestingly, cocaine exposure alone increased the spontaneous firing rate in the BLA to levels observed following chronic stress exposure in drug-naïve rats. Chronic stress exposure during cocaine withdrawal further increased firing rate. These studies may identify a potential mechanism by which both cocaine and chronic stress exposure drive cue-induced relapse vulnerability during abstinence.

BackgroundThe Institute of Medicine has called for actions to understand and target sex‐related differences in care and outcomes for out‐of‐hospital cardiac arrest patients. We assessed changes in bystander and first‐responder interventions and outcomes for males versus females after statewide efforts to improve cardiac arrest care.Methods and ResultsWe identified out‐of‐hospital cardiac arrests from North Carolina (2010–2014) through the CARES (Cardiac Arrest Registry to Enhance Survival) registry. Outcomes for men versus women were examined through multivariable logistic regression analyses adjusted for (1) nonmodifiable factors (age, witnessed status, and initial heart rhythm) and (2) nonmodifiable plus modifiable factors (bystander cardiopulmonary resuscitation and defibrillation before emergency medical services), including interactions between sex and time (ie, year and year2). Of 8100 patients, 38.1% were women. From 2010 to 2014, there was an increase in bystander cardiopulmonary resuscitation (men, 40.5%–50.6%; women, 35.3%–51.8%; P for each <0.0001) and in the combination of bystander cardiopulmonary resuscitation and first‐responder defibrillation (men, 15.8%–23.0%, P=0.007; women, 8.5%–23.7%, P=0.004). From 2010 to 2014, the unadjusted predicted probability of favorable neurologic outcome was higher and increased more for men (men, from 6.5% [95% confidence interval (CI), 5.1–8.0] to 9.7% [95% CI, 8.1–11.3]; women, from 6.3% [95% CI, 4.4–8.3] to 7.4% [95% CI, 5.5–9.3%]); while adjusted for nonmodifiable factors, it was slightly higher but with a nonsignificant increase for women (from 9.2% [95% CI, 6.8–11.8] to 10.2% [95% CI, 8.0–12.5]; men, from 5.8% [95% CI, 4.6–7.0] to 8.4% [95% CI, 7.1–9.7]). Adding bystander cardiopulmonary resuscitation and defibrillation before EMS (modifiable factors) did not substantially change the results.ConclusionsBystander and first‐responder interventions increased for men and women, but outcomes improved significantly only for men. Additional strategies may be necessary to improve survival among female cardiac arrest patients.

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Adolescence is a critical period of development with increased sensitivity toward psychological stressors. Many psychiatric conditions emerge during adolescence and animal studies have shown that that acute stress has long-term effects on hypothalamic-pituitary-adrenal axis function and behavior. We recently demonstrated that acute stress produces long-term electrophysiological changes in locus coeruleus and long-lasting anxiety-like behavior in adolescent male rats. Based on prior reports of increased stress sensitivity during adolescence and increased sensitivity of female locus coeruleus toward corticotropin releasing factor, we hypothesized that the same acute stressor would cause different behavioral and physiological responses in adolescent female and adult male and female rats one week after stressor exposure. In this study, we assessed age and sex differences in how an acute psychological stressor affects corticosterone release, anxiety-like behavior, and locus coeruleus physiology at short- and long-term intervals. All groups of animals except adult female responded to stress with elevated corticosterone levels at the acute time point. One week after stressor exposure, adolescent females showed decreased firing of locus coeruleus neurons upon current injection and increased exploratory behavior compared to controls. The results were in direct contrast to changes observed in adolescent males, which showed increased anxiety-like behavior and increased spontaneous and induced firing in locus coeruleus neurons a week after stressor exposure. Adult males and females were both behaviorally and electrophysiologically resilient to the long-term effects of acute stress. Therefore, there may be a normal developmental trajectory for locus coeruleus neurons which promotes stress resilience in adults, but stressor exposure during adolescence perturbs their function. Furthermore, while locus coeruleus neurons are more sensitive to stressor exposure during adolescence, the effect varies between adolescent males and females. These findings suggest that endocrine, behavioral, and physiological responses to stress vary among animals of different age and sex, and therefore these variables should be taken into account when selecting models and designing experiments to investigate the effects of stress. These differences in animals may also allude to age and sex differences in the prevalence of various psychiatric illnesses within the human population.