Social zeitgeber and sleep loss as risk factors for suicide in American Indian adolescents.

American Indians / Alaska Natives (AI/AN) bear a high burden of suicide, the reasons for which are not completely understood, and rates can vary by tribal group and location. This article aims to identify circumstances reported by a community group of American Indian adolescent participants to be associated with their depression and/or suicide. American Indian adolescents (n = 360) were recruited from contiguous reservations and were assessed with a semi-structured diagnostic interview. Twenty percent of the adolescents reported suicidal thoughts (ideation, plans), an additional 8% reported a history of suicide attempts, and three deaths due to suicide were reported. Suicidal behaviors and major depressive disorder (MDD) co-occurred and were more common among female adolescents. The distressing events that adolescents most often reported were: death in the family, family disruption, peer relationship problems, and school problems. All of these events were significantly associated with suicidal behaviors, however those with suicidal acts were more likely to report death in the family. Those with MDD but no suicidal behaviors were more likely to report disruptions in the family. Disruptions in falling asleep were also associated with suicidal behaviors and having experienced a death in the family. Disruptions in important relationships, particularly through death or divorce, may be interpreted as a loss or disruption in "social zeitgebers" that may in turn disturb biological rhythms, such as sleep, thus potentially increase the risk for MDD and/or suicide. Prevention programs aimed at ameliorating the impact of disruptions in important relationships may potentially reduce suicidal behaviors in AI/AN adolescents.

Use of a Fitbit-like device in rats: Sex differences, relation to EEG sleep, and use to measure the long-term effects of adolescent ethanol exposure.

BACKGROUND: Sleep difficulties and rhythm disturbances are some of the problems associated with adolescent binge drinking. Recently, animal models of alcohol-induced insomnia have been developed. However, studies in human subjects have recently focused not only on nighttime EEG findings but also on daytime sleepiness and disrupted activity levels as typically measured by activity tracking devices such as the "Fitbit." We sought to develop and test a Fitbit-like device (the "FitBite") in rats and use it to track rest-activity cycles following adolescent alcohol exposure. METHODS: The effects of 5 weeks of adolescent ethanol vapor or control conditions were evaluated in 48 male and female Wistar rats using FitBite activity while intoxicated, and during acute (24 h post-vapor exposure) and chronic withdrawal (4 weeks post-vapor exposure). Data were analyzed using activity count and cosinor analyses. Fourteen rats were subsequently implanted with cortical electrodes, and data from the FitBite were compared with EEG data to determine how well the FitBite could identify sleep and activity cycles. RESULTS: Female rats were generally more active than males, with higher circadian rhythm amplitudes and mesors (rhythm-adjusted means) across a 24-h period. There were significant correlations between EEG-estimated sleep and activity counts using the FitBite. When the rats were tested during intoxication after 4 weeks of ethanol vapor exposure, they had significantly less overall activity. Disruptions in circadian rhythm were also found with significant decreases in the circadian amplitude, mesor, and a later shift in the acrophase. At 24 h of ethanol withdrawal, rats had more episodes of activity with shorter durations during the daytime, when rats are expected to spend more of their time sleeping. This effect remained at 4 weeks following withdrawal, but circadian rhythm disruptions were no longer present. CONCLUSIONS: A Fitbit-like device can be successfully used in rats to assess rest-activity cycles. Adolescent alcohol exposure produced circadian rhythm disturbances that were not observed after withdrawal. Fragmentation of ultradian rest-activity cycles during the light period was found at 24 h and 4 weeks after withdrawal and support data demonstrating the presence of sleep disturbance long after alcohol withdrawal.

Correction to: Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence.

The title of this article is "Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence".

PSPH-D-18-00526: Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence.

RATIONALE: Sleep difficulties are one of the problems associated with adolescent binge drinking. However, the mechanisms underlying adolescent alcohol-associated sleep disturbances and potential targets for therapy remain under investigated. Orexin receptor antagonists may have therapeutic value in the treatment of insomnia, yet the use of this class of drugs in the treatment of sleep disturbances following adolescent alcohol exposure has not been studied. OBJECTIVES: This study employed a model whereby ethanol vapor exposure occurred for 5 weeks during adolescence (AIE), and waking event-related oscillations (EROs) and EEG sleep were subsequently evaluated in young adult rats. The ability of two doses (10, 30 mg/kg PO) of a dual orexin receptor antagonist (DORA-12) to modify sleep, EEG, and EROs was investigated in AIE rats and controls. RESULTS: Adolescent vapor exposure was found to produce a fragmentation of sleep, in young adults, that was partially ameliorated by DORA-12. DORA-12 also produced increases in delta and theta power in waking EROs recorded before sleep, and deeper sleep as indexed by increases in delta and theta power in the sleep EEG in both ethanol and control rats. Rats given DORA-12 also fell asleep faster than vehicle-treated rats as measured by a dose-dependent reduction in the latency to both the first slow wave and REM sleep episodes. CONCLUSIONS: This study showed that DORA-12 can affect the sleep disturbance that is associated with a history of adolescent ethanol exposure and also has several other sleep-promoting effects that are equivalent in both ethanol and control rats.

Phase locking of event-related oscillations is decreased in both young adult humans and rats with a history of adolescent alcohol exposure.

Alcohol exposure typically begins in adolescence, and frequent binge drinking has been associated with health risk behaviors including alcohol use disorders (AUDs). Few studies have documented the effects of a history of adolescent binge drinking on neurophysiological consequences in young adulthood. Synchrony of phase (phase locking (PL)) of event-related oscillations (EROs) within and between different brain areas reflects communication exchange between neural networks and is a sensitive measure of adolescent development in both rats and humans, and thus may be a good translational measure of the potential harmful effects of alcohol exposure during adolescence. In this study, EROs were collected from 1041 young adults of Mexican American and American Indian ancestry (age 18-30 years) with and without a history of adolescent binge drinking (five drinks for boys and four for girls per occasion at least once per month) and in 74 young adult rats with and without a history of 5 weeks of adolescent alcohol vapor exposure. PL of theta and beta frequencies between frontal and parietal cortex were estimated using an auditory-oddball paradigm in the rats and a visual facial expression paradigm in the humans. Significantly lower PL between frontal and parietal cortices in the theta frequencies was seen in both the humans and the rats with a history of adolescent alcohol exposure as compared with their controls. These findings suggest that alcohol exposure during adolescence may result in decreases in synchrony between cortical neuronal networks, suggesting a developmental delay, in young adult humans and in rats.

Effect of suvorexant on event-related oscillations and EEG sleep in rats exposed to chronic intermittent ethanol vapor and protracted withdrawal.

STUDY OBJECTIVES: Insomnia is a prominent complaint in patients with alcohol use disorders (AUD). However, despite the importance of sleep in the maintenance of sobriety, treatment options for sleep disturbance associated with a history of AUD are currently limited. Recent clinical trials have demonstrated that suvorexant, a dual Hct/OX receptor antagonist, normalizes sleep in patients with primary insomnia; yet, its potential for the treatment of sleep pathology associated with AUD has not been investigated in either preclinical or clinical studies. METHODS: This study employed a model whereby ethanol vapor exposure or control conditions were administered for 8 weeks to adult rats. Waking event-related oscillations (EROs) and EEG sleep were evaluated at baseline before exposure and again following 24 hr of withdrawal from the exposure. Subsequently, the ability of vehicle (VEH) and two doses (10, 30 mg/kg IP) of suvorexant to modify EROs, sleep, and the sleep EEG was investigated. RESULTS: After 24 hr following EtOH withdrawal, the ethanol-treated group had increases in waking ERO θ and ß activity, more fragmented sleep (shorter duration and increased frequency of slow wave (SW) and rapid eye movement [REM] sleep episodes), and increased θ and ß power in REM and SW sleep. Suvorexant induced a dose-dependent decrease in the latency to REM and SW sleep onsets but also produced REM and SW sleep fragmentation and increased ß energy in waking EROs when compared with VEH. CONCLUSIONS: Taken together, these studies suggest that suvorexant has overall sleep-promoting effects, but it may exacerbate some aspects of sleep and EEG pathology.

Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats.

RATIONALE: γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA(B) receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA(B) receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABA(B) receptor agonists, GABA(B) receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists. OBJECTIVES AND METHODS: We examined whether the acute effects of the GABA(B) receptor positive modulator N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self-administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined. RESULTS: Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period. CONCLUSIONS: These results showed that BHF177 selectively blocked nicotine self-administration and prevented cue-induced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABA(B) receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans.