Acute exposure to a salient stressor, such as in post-traumatic stress disorder, can have lasting impacts upon an individual and society. To study stress in rodents, some naturalistic methods have included acute exposure to a predator odor, such as the synthetic fox odor 2,4,5, trimethyl-3-thiazoline (TMT). These experiments explore the stress-related behaviors and cortical activity induced by TMT exposure in adult male C57BL/6J mice and the influence of the stress neuropeptide corticotropin-releasing factor (CRF) on these responses. Compared to H 2 O and a novel odorant, vanilla, mice exposed to TMT in the home cage showed increased avoidance and defensive burying indicative of evident stress responses. Consistent with stress-induced activation of the medial prefrontal cortex (mPFC), we found that the prelimbic (PL) and infralimbic (IL) subregions of the mPFC had elevated c-Fos immunolabeling after TMT and vanilla compared to H 2 O. Slice physiology recordings were performed in layers 2/3 and 5 of the PL and IL, following TMT, vanilla, or H 2 O exposure. In TMT mice, but not vanilla or H 2 O mice, PL layers 2/3 showed heightened spontaneous excitatory post-synaptic currents and synaptic drive, suggesting TMT enhanced excitatory transmission. Synaptic drive in PL was increased in both TMT and H 2 O mice following bath application of 300 nM CRF, but only H 2 O mice increased excitatory currents with 100 nM CRF, suggesting dose-effect curve shifts in TMT mice. Further, systemic pretreatment with the CRF-R1 antagonist CP154526 and bath application with the CRF-R1 antagonist NBI27914 reduced excitatory transmission in TMT mice, but not H 2 O mice. CP154526 also reduced stress-reactive behaviors induced by TMT. Taken together, these findings suggest that exposure to TMT leads to CRF-R1 driven changes in behavior and changes in synaptic function in layer 2/3 neurons in the PL, which are consistent with previous findings that CRF-R1 in the mPFC plays an important role in predator odor-related behaviors.Neuropsychopharmacology (2019) 44:766-775; https://doi.

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.

The effect of steady state therapeutic theophylline serum levels on lithium clearance was investigated. A significant increase in lithium clearance occurred with the administration of theophylline. Despite considerable intersubject variability, a direct lithium clearance estimation method demonstrated a mean increase of 30% with the addition of theophylline. The concomitant use of lithium and theophylline potentially may alter lithium levels sufficiently to result in manic or depressive relapses in patients receiving lithium prophylactically.

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor (KOR) signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate promoting a maladaptive behavioral phenotype following heavy alcohol drinking.Altered responses to an innate stressor were associated with enhanced PFC-driven excitation of prodynorphin-containing neurons in the BNST during protracted withdrawal from intermittent alcohol drinking. These findings suggest that corticolimbic connectivity may underlie impaired stress-coping during protracted withdrawal from heavy drinking and represents a target of potential therapeutic mediation.BNST PDYN alcohol-induced stress deficit 2 Author ContributionsLSH, SN, CS, EK, and RC performed and analyzed behavioral tests. LSH, MEF, and OH provided support for and analyzed the fiber photometry experiments. LSH, SN, MMP, and DP assisted with electrophysiology experiments. WY and KB provided additional technical expertise. LSH and TLK conceptualized, designed the study, and wrote the manuscript.