Biology subjects

Palmer, A. A.

Publications and source records attributed to Palmer, A. A..

76 records · Page 5Linked to original sources

bioRxiv2017

Glyoxalase (GLO1) inhibition or genetic overexpression does not alter ethanol locomotor effects: implications for GLO1 as a therapeutic target in alcohol use disorders

BackgroundGlyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol drinking. The present study assessed whether inhibition of GLO1, or genetic over expression of Glo1, would also alter the locomotor effects of ethanol, which might explain reduced ethanol consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control.\n\nMethodsMale C57BL/6J mice were pretreated with aeither the GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG; 7.5 mg/kg; Experiment 1) or muscimol (0.75 mg/kg; Experiment 2), or their corresponding vehicle. We then determined whether locomotor response to a range of ethanol doses (0, 0.5, 1.0, 1.5, 2.0, and 2.5) was altered by either pBBG or muscimol pretreatment. We also examined the locomotor response to a range of ethanol doses in FVB/NJ wild type and transgenic Glo1 over expressing mice (Experiment 3). Anxiety-like behavior (time spent in the center of the open field) was assessed in all three experiments.\n\nResultsThe ethanol dose-response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1. In contrast, muscimol blunted locomotor stimulation at low ethanol doses, and potentiated locomotor sedation at higher ethanol doses. No drug or genotype differences were seen in anxiety-like behavior after ethanol treatment.\n\nConclusionsThe dose of pBBG used in this study is within the effective range shown previously to reduce ethanol drinking. Glo1 overexpression has been previously shown to increase ethanol drinking. However, neither manipulation altered the dose response curve for ethanols locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of ethanol. The present data demonstrate that reduced ethanol drinking caused by GLO1 inhibition is not due to potentiation of ethanols stimulant or depressant effects.

neuroscience↗

bioRxiv2017

Genome wide association study of behavioral, physiological and gene expression traits in a multigenerational mouse intercross

The LG/J x SM/J advanced intercross line of mice (LG x SM AIL) is a multigenerational outbred population. High minor allele frequencies, a simple genetic background, and the fully sequenced LG and SM genomes make it a powerful population for genome-wide association studies. Here we use 1,063 AIL mice to identify 126 significant associations for 50 traits relevant to human health and disease. We also identify thousands of cis- and trans-eQTLs in the hippocampus, striatum, and prefrontal cortex of [~]200 mice. We replicate an association between locomotor activity and Csmd1, which we identified in an earlier generation of this AIL, and show that Csmd1 mutant mice recapitulate the locomotor phenotype. Our results demonstrate the utility of the LG x SM AIL as a mapping population, identify numerous novel associations, and shed light on the genetic architecture of mammalian behavior.

genetics↗

bioRxiv2017

Genome-wide association study of Alcohol Use Disorder Identification Test (AUDIT) scores in 20,328 research participants of European ancestry

Genetic factors contribute to the risk for developing alcohol use disorder (AUD). In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association (GWAS) study of the Alcohol Use Disorder Identification Test (AUDIT), an instrument designed to screen for alcohol misuse over the past year. Our final sample consisted of 20,328 research participants of European ancestry (55.3% females; mean age = 53.8, SD = 16.1) who reported ever using alcohol. Our results showed that the chip-heritability of AUDIT score, when treated as a continuous phenotype, was 12%. No loci reached genome-wide significance. The gene ADH1C, which has been previously implicated in AUD, was among our most significant associations (4.4 x 10-7; rs141973904). We also detected a suggestive association on chromosome 1 (2.1 x 10-7; rs182344113) near the gene KCNJ9, which has been implicated in mouse models of high ethanol drinking. Using LD score regression, we identified positive genetic correlations between AUDIT score and AUD, high alcohol consumption, and cigarette smoking. We also observed an unexpected positive genetic correlation between AUDIT and educational attainment, and additional unexpected negative correlations with BMI/obesity and attention-deficit/hyperactivity disorder (ADHD). We conclude that conducting a genetic study using data from a population unselected for AUD and responding to an online questionnaire may represent a cost-effective strategy for elucidating the etiology of AUD.

genetics↗

bioRxiv2017

Genetics of the Research Domain Criteria (RDoC): genome-wide association study of delay discounting

Delay discounting (DD), which is the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated SNP was rs6528024 (P = 2.40 x 10-8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype, and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition, and body weight.

genetics↗