Laboratory-induced stress produces elevations in cortisol and deficits in memory, especially when stress is induced immediately before retrieval of emotionally valent stimuli. Sex and sex steroids appear to influence these stress-induced outcomes, though no study has directly compared the effects of laboratory-induced stress on cortisol and emotional retrieval across the menstrual cycle. We examined the effect of psychosocial stress on cortisol responsivity and emotional retrieval in women tested during either the follicular phase (low estradiol and progesterone) or the luteal phase (higher estradiol and progesterone). Forty women (50%White; age 18–40 years) participated in the study; 20 completed the task during the luteal phase and 20 during the follicular phase. Psychosocial stress was induced with the Trier Social Stress Test (TSST). On the day before the TSST, participants learned two lists of word pairs to 100% criterion. The next day, participants recalled one list after the control condition and the other after the TSST. Women in the follicular phase, but not the luteal phase, demonstrated a significant cortisol response to the TSST. There was a stress-induced decrease in emotional retrieval following the TSST, but this effect was not modified by menstrual phase. However, regression and correlational analyses showed that individual differences in stress-induced cortisol levels were associated with impaired emotional retrieval in the follicular phase only. The present findings indicate that cortisol responsivity and the impairing effects of cortisol on emotional memory are lower when levels of estradiol and progesterone are high compared to when levels are low.

Alcohol excitation of the ventral tegmental area (VTA) is important in neurobiological processes related to the development of alcoholism. The ionotropic receptors on VTA neurons that mediate ethanol-induced excitation have not been identified. Quinidine blocks ethanol excitation of VTA neurons, and blockade of two-pore potassium channels is among the actions of quinidine. Therefore two-pore potassium channels in the VTA may be potential targets for the action of ethanol. Here, we explored whether ethanol activation of VTA neurons is mediated by the twopore potassium channel KCNK13. Extracellular recordings of the response of VTA neurons to ethanol were performed in combination with knockdown of Kcnk13 using a short hairpin RNA (shRNA) in C57BL/6J mice. Real-time PCR and immunohistochemistry were used to examine expression of this channel in the VTA. Finally, the role of KCNK13 in binge-like drinking was examined in the drinking in the dark test after knockdown of the channel. Kcnk13 expression in the VTA was increased by acute ethanol exposure. Ethanol-induced excitation of VTA neurons was selectively reduced by shRNA targeting Kcnk13. Importantly, knockdown of Kcnk13 in the VTA resulted in increased alcohol drinking. These results are consistent with the idea that ethanol stimulates VTA neurons at least in part by inhibiting KCNK13, a specific two-pore potassium channel, and that KCNK13 can control both VTA neuronal activity and binge drinking. KCNK13 is a novel alcohol-sensitive molecular target and may be amenable to the development of pharmacotherapies for alcoholism treatment.

BackgroundChronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive‐like alcohol intake. GR antagonism can prevent dependence‐induced escalation in drinking, but very little is known about the role of GR in regulating high‐risk nondependent alcohol intake. Here, we investigate the role of GR in regulating binge‐like drinking and aversive responses to alcohol in the High Drinking in the Dark (HDID‐1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) in the Drinking in the Dark (DID) test, and in their founder line, the HS/NPT.MethodsIn separate experiments, male and female HDID‐1 mice were administered one of several compounds that inhibited GR or its negative regulator, FKBP51 (mifepristone [12.5, 25, 50, 100 mg/kg], CORT113176 [20, 40, 80 mg/kg], and SAFit2 [10, 20, 40 mg/kg]) during a 2‐day DID task. EtOH consumption and BECs were measured. EtOH conditioned taste and place aversion (CTA and CPA, respectively) were measured in separate HDID‐1 mice after mifepristone administration to assess GR’s role in regulating the conditioned aversive effects of EtOH. Lastly, HS/NPT mice were administered CORT113176 during DID to assess whether dissimilar effects from those of HDID‐1 would be observed, which could suggest that selective breeding had altered sensitivity to the effects of GR antagonism on binge‐like drinking.ResultsGR antagonism (with both mifepristone and CORT113176) selectively reduced binge‐like EtOH intake and BECs in the HDID‐1 mice, while inhibition of FKBP51 did not alter intake or BECs. In contrast, GR antagonism had no effect on EtOH intake or BECs in the HS/NPT mice. Although HDID‐1 mice exhibit attenuated EtOH CTA, mifepristone administration did not enhance the aversive effects of EtOH in either a CTA or CPA task.ConclusionThese data suggest that the selection process increased sensitivity to GR antagonism on EtOH intake in the HDID‐1 mice, and support a role for the GR as a genetic risk factor for high‐risk alcohol intake.

Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol.