Chronic Voluntary Alcohol Drinking Causes Anxiety-like Behavior, Thiamine Deficiency, and Brain Damage of Female Crossed High Alcohol Preferring Mice

Abstract

The central nervous system is vulnerable to chronic alcohol abuse, and alcohol dependence is a chronically relapsing disorder which causes a variety of physical and mental disorders. Appropriate animal models are important for investigating the underlying cellular and molecular mechanisms. The crossed High Alcohol Preferring mice prefer alcohol to water when given free access. In the present study, we used female cHAP mice as a model of chronic voluntary drinking to evaluate the effects of alcohol on neurobehavioral and neuropathological changes. The female cHAP mice had free-choice access to 10% ethanol and water, while control mice had access to water alone at the age of 60-day-old. The mice were exposed to alcohol for 7 months then subjected to neurobehavioral tests including open field (OF), elevated plus maze (EPM), and Morris water maze (MWM). Results from OF and EPM tests suggested that chronic voluntary drinking caused anxiety-like behaviors. After behavior tests, mice were sacrificed, and brain tissues were processed for biochemical analyses. Alcohol altered the levels of several neurotransmitters and neurotrophic factors in the brain including gamma-Aminobutyric acid (GABA), corticotropin-releasing factor, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor. Alcohol increased the expression of neuroinflammation markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and C-C chemokine receptor 2 (CCR2). Alcohol also induced cleaved caspase-3 and glial fibrillary acidic protein, indicative of neurodegeneration and gliosis. In addition, alcohol inhibited the expression of thiamine transporters in the brain and reduced thiamine levels in the blood. Alcohol also caused oxidative stress and endoplasmic reticulum (ER) stress, and stimulated neurogenesis.

Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:Tdtomato Transgenic Rats

“…Notably, there were no group effects of EtOH drinking on pain sensitivity or affective behavior. While previous studies have seen effects of EtOH on pain sensitivity and affect (Quadir et al, 2021b) (Gong et al, 2017;Overstreet et al, 2005;Van Skike et al, 2015;Xu et al, 2021), others studies have not (Bloch et al, 2020;McNamara and Ito, 2021;Pirino et al, 2022) One potential explanation is that rats in the present study only drank for 3-4 weeks before behavioral testing and thus did not consume enough EtOH to produce behavioral deficits. Studies in Wistar rats report escalated intake after ~20 EtOH drinking sessions (Carnicella et al, 2009;George et al, 2012;Kimbrough et al, 2017); rats in this study only drank for 16 sessions.…”

Alcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review

“…An animal study using crossed high alcohol-preferring mice reported that chronic voluntary drinking caused anxiety-like behaviors. Alcohol increased the expression of neuroinflammation markers and induced oxidative stress and endoplasmic reticulum stress [ 48 ]. Clinical and rodent studies have studied the acute and chronic effects of alcohol on glutathione levels.…”

Neurokinin‐1 receptor antagonist rolapitant suppresses anxiety and alcohol intake produced by repeated withdrawal episodes

“…Indeed, NK1r antagonists have been found to exert anxiolytic‐like effects [20], although less pronounced than those reported for benzodiazepines [21]. It is well known that chronic alcohol consumption increases stress reactivity [22,23] and promotes anxiety disorders [24], which, in turn, contributes to the maintenance of and relapse to pathological alcohol use [25]. NK1r antagonists have been reported to reduce stress‐associated alcohol‐seeking [14].…”