Molecular and neurologic responses to chronic alcohol use

Abstract

This chapter provides an overview of current knowledge on the molecular and clinical aspects of chronic alcohol effects on the central nervous system. This drug is almost ubiquitous, widely enjoyed socially, but produces a diverse spectrum of neurologic disease when abused. Acutely, alcohol interacts predominantly with γ-aminobutyric acid-A (GABA-A) and N-methyl-d-aspartate (NMDA) receptors, but triggers diverse signaling events within well-defined neural pathways. These events result in adaptive changes in gene expression that ultimately produce two major states: addiction and toxicity. Epigenetic modifications of chromatin could lead to long-lived or even transgenerational changes in gene expression, thus producing aspects of the heritability of alcohol use disorders (AUD) and long-term behaviors such as recidivism. The diverse clinical syndromes produced by chronic alcohol actions in the central nervous system reflect the molecular pathology and predominantly involve aspects of tolerance/withdrawal, selective vulnerability (manifest as central pontine myelinolysis, Marchiafava-Bignami disease), and additional environmental factors (e.g., thiamine deficiency in Wernicke-Korsakoff's syndrome). Additionally, deleterious aspects of chronic alcohol on signaling, synaptic transmission, and cell toxicity lead to primary alcoholic dementia. Genetically determined aspects of myelin structure and alcohol actions on myelin gene expression may be a prominent molecular mechanism resulting in a predisposition to, or causation of, AUD and multiple other neurologic complications of chronic alcohol. The dramatic progress made in understanding molecular actions of alcohol holds great promise for our eventual treatment or prevention of AUD and neurologic complications resulting from chronic alcohol abuse.

Keywords: Alcoholism; molecular mechanisms; neurologic complications.

Fig. 10.1

Overview of molecular adaptive events leading to alcoholism and neurologic complications of alcohol use disorders (AUD). The figure documents major aspects of current knowledge regarding behavioral, systems biology, and molecular mechanisms leading from acute alcohol exposure to chronic consequences such as AUD and neurologic complications. Schema are illustrative only and not meant to be all-inclusive. Acute alcohol has major direct effects on ion channels (γ-aminobutyric acid A (GABA-A), N-methyl-D-aspartate (NMDA), and K⁺). Alcohol-induced release of dopamine (DA) is a major factor in the rewarding properties of the drug. Alteration in numerous signaling cascades (e.g., cAMP, PI-3-kinase (PI3K), and protein kinase C (PKC)) and transcription factors (GR, glucocorticoid receptor; CREB; and Nfkb, Nf-kappa-B) may function in acute and chronic neuroplasticity by altering gene expression at the transcriptional, translational, or posttranslational level. Gene expression alterations are thought to play a central role in both acute and chronic neuroadaptation to alcohol. Epigenetic changes (DNA or histone modifications) are proposed as a mechanism underlying persistence of gene expression/neuroadaptive events, leading to clinical sequelae such as compulsive drinking, recidivism, and alcohol-related neurologic disease. BDNF, brain-derived neurotropic factor; NPY, neuropeptide Y; CRF, corticotropin-releasing factor; GDNF, glial cell-derived neurotropic factor.

Fig. 10.2

Hypothetic scheme for the role of myelin in alcoholism and alcohol-related neurologic disorders. Basal myelin expression is pictured as affecting initial sensitivity to alcohol, such as with loss-of-righting reflex (LORR), and perhaps relatedly, alcohol consumption. Acute alcohol, however, also alters myelin gene expression, which may contribute to frontal-lobe dysfunction and the consequent development of abusive alcohol consumption. Chronic alcohol exposure produces prominent decreases in myelin gene expression and myelin structural abnormalities. These are envisioned as contributing to frontal-lobe dysfunction in alcoholism and alcoholic dementia. Additionally, alcohol-induced myelin pathology may contribute as a risk factor to other alcohol-related neurologic diseases, such as Wernicke–Korsakoff’s syndrome (WKS), Machiafava–Bignami disease (MBD), central pontine myelinolysis (CPM), and cerebellar degeneration (CD).