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Scn4b regulates the hypnotic effects of ethanol and other sedative drugs.

ABSTRACT: The voltage-gated sodium channel subunit ?4 (SCN4B) regulates neuronal activity by modulating channel gating and has been implicated in ethanol consumption in rodent models and human alcoholics. However, the functional role for Scn4b in ethanol-mediated behaviors is unknown. We determined if genetic global knockout (KO) or targeted knockdown of Scn4b in the central nucleus of the amygdala (CeA) altered ethanol drinking or related behaviors. We used four different ethanol consumption procedures (continuous and intermittent two-bottle choice (2BC), drinking-in-the dark and chronic intermittent ethanol vapor) and found that male and female Scn4b KO mice did not differ from their wild-type (WT) littermates in ethanol consumption in any of the tests. Knockdown of Scn4b mRNA in the CeA also did not alter 2BC ethanol drinking. However, Scn4b KO mice showed longer duration of the loss of righting reflex induced by ethanol, gaboxadol, pentobarbital and ketamine. KO mice showed slower recovery to basal levels of handling-induced convulsions after ethanol injection, which is consistent with the increased sedative effects observed in these mice. However, Scn4b KO mice did not differ in the severity of acute ethanol withdrawal. Acoustic startle responses, ethanol-induced hypothermia and clearance of blood ethanol also did not differ between the genotypes. There were also no functional differences in the membrane properties or excitability of CeA neurons from Scn4b KO and WT mice. Although we found no evidence that Scn4b regulates ethanol consumption in mice, it was involved in the acute hypnotic effects of ethanol and other sedatives.

SUBMITTER: Blednov YA

PROVIDER: S-EPMC6612599 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Scn4b regulates the hypnotic effects of ethanol and other sedative drugs.

Blednov Yuri A YA Bajo Michal M Roberts Amanda J AJ Da Costa Adriana J AJ Black Mendy M Edmunds Stephanie S Mayfield Jody J Roberto Marisa M Homanics Gregg E GE Lasek Amy W AW Hitzemann Robert J RJ Harris Robert A RA

Genes, brain, and behavior 20190502 6

The voltage-gated sodium channel subunit β4 (SCN4B) regulates neuronal activity by modulating channel gating and has been implicated in ethanol consumption in rodent models and human alcoholics. However, the functional role for Scn4b in ethanol-mediated behaviors is unknown. We determined if genetic global knockout (KO) or targeted knockdown of Scn4b in the central nucleus of the amygdala (CeA) altered ethanol drinking or related behaviors. We used four different ethanol consumption procedures ( ...[more]

PMID: 30817077

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Project description:IntroductionOpioid and sedative/hypnotic drug overdoses are major causes of morbidity in the U.S. This study compares 12-month incidence of fatal unintentional drug overdose, suicide, and other mortality among emergency department patients presenting with nonfatal opioid or sedative/hypnotic overdose.MethodsThis is a retrospective cohort study using statewide, longitudinally linked emergency department patient record and mortality data from California. Participants comprised all residents presenting to a licensed emergency department at least once in 2009-2011 with nonfatal unintentional opioid overdose, sedative/hypnotic overdose, or neither (a 5% random sample). Participants were followed for 1 year after index emergency department presentation to assess death from unintentional overdose, suicide, or other causes, ascertained using ICD-10 codes. Absolute death rates per 100,000 person years and standardized mortality ratios relative to the general population were calculated. Data were analyzed February-August 2019.ResultsFollowing the index emergency department visit, unintentional overdose death rates per 100,000 person years were 1,863 following opioid overdose, 342 following sedative/hypnotic overdose, and 31 for reference patients without an index overdose (respective standardized mortality ratios of 106.1, 95% CI=95.2, 116.9; 24.5, 95% CI=21.3, 27.6; and 2.6, 95% CI=2.2, 3.0). Suicide mortality rates per 100,000 were 319, 174, and 32 following opioid overdose, sedative/hypnotic overdose, and reference visits, respectively. Natural causes mortality rates per 100,000 were 8,058 (opioid overdose patients), 17,301 (sedative/hypnotic overdose patients), and 3,097 (reference patients).ConclusionsEmergency department patients with nonfatal opioid or sedative/hypnotic drug overdose have exceptionally high risks of death from unintentional overdose, suicide, and other causes. Emergency department-based interventions offer potential for reducing these patients' overdose and other mortality risks.

Project description:BackgroundBenzodiazepines and sedative-hypnotic drugs (BZD/SHDs), such as zopiclone and the antidepressant trazodone, pose risks such as falls, fractures, and confusion, especially for older adults. Use of these drugs in the acute care setting is poorly understood.ObjectivesTo determine the point prevalence and characteristics of use of BZD/SHDs in hospitals in Nova Scotia, Canada.MethodsA point prevalence survey was conducted for adults admitted to all hospitals with at least 30 acute care beds between May and August 2016. Drugs administered intravenously, patients in long-term care, and patients receiving mental health services, addiction treatment, or critical care were excluded. The proportion of included patients who had received a BZD/SHD within the 24 h before the start of the survey was determined. A descriptive statistical analysis was performed.ResultsOverall BZD/SHD prevalence was 34.6% (487/1409) across the 16 eligible hospitals. The average age was 70.3 years, and 150 (30.8%) of the patients were 80 years or older. Among the 585 prescriptions for these patients, commonly used drugs were zopiclone (32.0%), lorazepam (21.9%), and trazodone (21.9%). The most common indications for use were bedtime/daytime sedation (60.0%) and anxiety (12.5%). More than half of the prescriptions (55.7%) had been initiated at home, 37.6% were started in hospital, and the place of initiation was unknown for 6.7%. Benzodiazepines were prescribed more frequently to patients under 65 years than those 80 years or older (41.3% versus 22.2%, p < 0.001) whereas trazodone was more frequently prescribed to the older of these 2 age groups (52.7% versus 14.3%, p < 0.001).ConclusionsBZD/SHDs were frequently used by hospitalized adult patients in Nova Scotia. Trazodone appears to have been substituted for benzodiazepines in the oldest age group. Pharmacists should direct their efforts toward preventing inappropriate initiation of BZD/SHDs in hospital, particularly for elderly patients.

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Scn4b regulates the hypnotic effects of ethanol and other sedative drugs.

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Scn4b regulates the hypnotic effects of ethanol and other sedative drugs.

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