Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats

Abstract

Background Binge-drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including increased pain, fear and anxiety. The periaqueductal gray (PAG) is involved in processing pain, fear and anxiety. The effects of adolescent binge drinking on gene expression in this region have yet to be studied. Methods Male adolescent P (alcohol preferring) rats were exposed to repeated binge-drinking (three 1-h sessions/day during the dark-cycle, 5 days/week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5 – 3 g/kg/session). We used RNA sequencing to assess the effects of ethanol intake on gene expression. Results Ethanol significantly altered expression of 1670 of the 12,123 detected genes: 877 (53%) decreased. In the glutamate system, 23 genes were altered, including reduction in 7 of 10 genes for metabotropic and NMDA receptors. Subunit changes in the NMDA receptor may make it less sensitive to ethanol. Changes in GABAA genes would most likely increase the ability of the PAG to produce tonic inhibition. Five serotonin receptor genes, 6 acetylcholine receptor genes and 4 glycine receptor genes showed decreased expression in the alcohol drinking rats. Opioid genes (e.g., Oprk1, Oprm1) and genes for neuropeptides linked to anxiety and panic behaviors (e.g., Npy1r) had mostly decreased expression. Genes for 27 potassium, 10 sodium and 5 calcium ion channels were differentially expressed. Nine genes in the cholesterol synthesis pathway had decreased expression, including Hmgcr, encoding the rate limiting enzyme. Genes involved in the production of myelin also had decreased expression. Conclusion The results demonstrate that binge-alcohol drinking during adolescence produces developmental changes in the expression of key genes within the PAG; many of these changes point to increased susceptibility to pain, fear and anxiety, which could contribute to excessive drinking to relieve these negative effects.

Rat animal models for screening medications to treat alcohol use disorders

“… 30 Bell et al, 2006a, 2009, 2016; McBride et al, 2010, 2013a, 2014a; McClintick et al, 2015, 2016; Obara et al, 2009; Rodd et al, 2008; Sari et al, 2006; …”

Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism

“…It alters their membranes as well as their ion channels, enzymes, N ‐methyl‐ d ‐aspartate (NMDA), and gamma‐aminobutyric acid (GABA) receptors. There are numerous reports showed EtOH action is directly associated with neurotransmitters such as dopamine, serotonin, GABA, NMDA, and its receptors (Benjamin et al., ; Fernando, ; George et al., , , ; McClintick et al., ; Spencer et al., ). Primary mechanism by which EtOH affects the brain is through regulation of neurotransmitters and ligands, voltage‐gated channels that are essential for neuronal excitability and synaptic function (Hoffman, ).…”

“…Long‐term alcohol exposure causes widespread changes in brain gene expression in humans and animal models (George et al., ; McClintick et al., ; Xiang et al., ). Many of these contribute to cellular adaptations which leads to changes in DNA and histone methylation, histone acetylation, and microRNA expression that affect expression of multiple genes in various types of brain cells (i.e., neurons and glia) that contribute to brain pathology and brain plasticity associated with alcohol abuse.…”

Wellbeing of Alcohol-preferring Rats Euthanized with Carbon Dioxide at Very Low and Low Volume Displacement Rates

“…3 This rat stock is generally more anxious and more prone to stress-induced changes in manipulation, especially when not habituated to handling, than are other lines. 19 Both male (24 rats; age, 108 to 399 d [mean, 213 d]) and female (24 rats; age, 130 to 276 d [mean, 189 d]) rats were used in this study. These animals were surplus offspring from the campus production colony, and none had been used for any other research project prior to enrollment in this euthanasia project.Husbandry.…”