PM297. High-dose zolpidem dependence and detoxification from withdrawal symptoms using diazepam Article Swipe

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Zolpidem Detoxification (alternative medicine) Diazepam Medicine Anesthesia Pharmacology Insomnia Alternative medicine Pathology

Joel Gelernter , Tom P. Freeman , Rebecca Pope , Matthew B. Wall , James A. Bisby , Maartje Luijten , Chandni Hindocha , Will Lawn , Claire Mokrysz , Abigail Moss , Michael Bloomfield , Celia J. A. Morgan , David Nutt , Valerie H. Curran ·

YOU? · · 2016 · Open Access · · DOI: https://doi.org/10.1093/ijnp/pyw041.297 · OA: W4238282673

Objective: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures.Although previous studies of AW and relapse have highlighted the critical importance of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and the detrimental role of stress, little is known about genetic risk factors.We therefore conducted genetic and neurobiological studies to identify and characterize novel risk loci.Methods: We performed a genome-wide association study (GWAS) of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent subjects, and bioinformatic analyses.We used genetically modified mouse neuronal cultures to conduct electrophysiological and pharmacological studies of neurobiological systems implicated by the GWAS.Results: The top association signal for AW severity was in sortilin-related gene SORCS2 on chromosome 4 (European-American meta-analysis n = 1,478, P = 4.3 x 10 -9 ), and the same risk allele also predicted more severe clinical outcomes in seizure disorder patients participating in a randomized trial of anticonvulsant effectiveness (n = 654, P = 3.2 x 10 -3 ).In humans, SORCS2 is most highly expressed in the nervous system, and bioinformatic analyses showed that the SORCS2 risk haplotype disrupts transcription factor (TF) binding motifs within a stress hormoneregulated enhancer element active in human hippocampus.In mouse hippocampal preparations, we demonstrate that SorCS2 is a key regulator of GluN2B-mediated synaptic responses.Conclusion: These translational findings identify new synaptic regulatory processes, and provide novel targets for managing the aversive consequences of abrupt alcohol cessation. PM297High-dose zolpidem dependence and detoxification from withdrawal symptoms using diazepam