Alcoholism is a chronic disease characterized by trouble controlling the consumption of alcohol, dependence (needing to consume more to achieve the same effects), and withdrawal upon rapid cessation of drinking. According to ARDI reports approximately 88,000 people had alcohol-related deaths in the United States between the years of 2006 and 2010. Furthermore, chronic alcohol use is consistently the third leading cause of death in the United States. In consequence, research has sought to determine the factors responsible for the development and persistence of alcoholism. From this research, several molecular and epigenetic mechanisms have been discovered.
Background Alcoholism is characterized by a wide range of symptoms including compulsive alcohol seeking and consumption, tolerance (resistance to the effects of alcohol after repeated consumption), and withdrawal symptoms such as irritability, profuse sweating, and uncontrollable shaking upon rapid cessation of drinking. There is not a specific test for diagnosing alcoholism; however, patient questionnaires and medical screenings for ailments typically associated with alcoholism, such as cirrhosis, heart problems, and pancreatitis, are often used as diagnostic tools. Several factors influence the development of alcoholism including genetic predisposition and environmental stressors such as grief, stress, depression, and anxiety. In coordination with these factors, molecular and epigenetic mechanisms influence the progression toward alcoholism.
Mechanisms An increased propensity for alcoholism has been associated with stress-related anxiety and dysphoria, a state of general unease or dissatisfaction. The experience of various types of stress, including severe acute stress and chronic stress, can lead to the onset of dysphoria. Ethanol consumption promotes the release of dopamine into the nucleus accumbens (NAc) which is translated as a “reward". Thus, to cope with negative emotions, individuals often turn to alcohol as a form of temporary self-medication. Unfortunately, repeated ethanol use results in diminishing returns which prompts increased intake and dependence. Research has and continues to investigate the molecular and epigenetic mechanisms underlying the downward spiral of alcoholism.
Molecular Mechanisms
Receptors Several receptors directly interact with ethanol to promote a cascade of signaling. N-methyl-D-aspartate (NMDA) receptors are glutamate receptors particularly important in long-term potentiation in neurons. These receptors have been linked to ethanol use. Acute ethanol exposure, a brief period of ethanol use, inhibits Ca2+ flow through NMDA receptors in the hippocampus, the brain structure particularly important in memory formation. A specific subunit of NMDA receptors, NR2B, shows particularly high sensitivity to ethanol as exemplified by increased NR2B expression in response to ethanol. Another family of receptors, metabotropic glutamate receptors (mGluR), may also contribute by activating MAPK pathways and increasing intracellular Ca2+. Antagonism of mGluR5 showed a decrease in ethanol consumption suggesting mGluR5's role in alcoholism. Furthermore, voltage-gated calcium channels (VGCCs) were shown to be inhibited by ethanol resulting in reduced influx of Ca2+. Yet, repeated ethanol intake, or chronic ethanol use, increases expression of the slow-inactivating L-type VGCCs known to sustain Ca2+ influx. When these channels are inhibited with an antagonist, ethanol consumption is reduced.
Adenylyl Cyclase Adenylyl cyclase (AC) plays a role in ethanol induced signaling pathways. Acute ethanol may increase AC activity resulting in increased levels of cAMP and altered activity of cAMP targets. Of the cAMP targets, protein kinase A (PKA) has been associated with ethanol use. While acute ethanol use increases the activity of AC, chronic use tends to desensitize AC such that more simulation, increased ethanol consumption, is required to elicit the same response.
Kinases Ethanol transduction pathways involve several protein kinases known to phosphorylate substrates linked to alcoholism, namely cAMP response element-binding protein (CREB). CREB plays a central role in ethanol responses making its activation an important step in the pathway. Some of the kinase families currently linked to alcoholism are Ca2+/calmodulin-dependent protein kinases (CaMKs), protein kinase A (PKA), and mitogen-activated protein kinases (MAPKs).
CamK Rapid changes in Ca2+ concentration, influenced by receptors such as those described above, regulate the activity of CaMKs. Withdrawal following chronic ethanol use as well as voluntary ethanol intake, consuming ethanol when both an ethanol solution and water are offered, in rats showed a decrease in CaMKIV and consequently p-CREB. In contrast, ethanol activates CaMKII resulting in phosphorylation of CaMKII targets such as BK potassium channels. PKA As discussed above, cAMP levels rise following ethanol-induced activation of AC. This rise in cAMP activates PKA. In response to acute ethanol exposure, activated PKA is transported to the nucleus where it phosphorylates CREB. While chronic ethanol use has not been shown to affect the levels of the catalytic domain PKA-Cα, voluntary ethanol intake does increase PKA-Cα in the central nucleus of the amygdala (CeA) and medial nucleus of the amygdala (MeA) in P rats. The increase in PKA levels following acute ethanol use may induce negative feedback mechanisms to reduce PKA activity. Chronic ethanol exposure has been shown to reduce PKA activity in the nucleus accumbens and the amygdala due to increased levels of PKA inhibitor α. MAPK MAPK proteins, especially Erk1/2, have been linked to ethanol use. While there is not a consensus, acute and chronic ethanol exposure may increase p-Erk1/2 levels in the CeA and MeA of rats. In contrast, a decrease in Erk1/2 is observed during withdrawal. These patterns are mirrored in Erk1/2’s downstream target CREB and serve as a link between ethanol exposure and CREB. Erk1/2 is activated in the CeA and ventral tegmental area (VTA) by GDNF, a downstream target of CREB, which was shown to decrease ethanol consumption. This likely serves as a negative-feedback mechanism to prevent excessive ethanol use.
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