Academic journal article Alcohol Research: Current Reviews

Circadian Genes, the Stress Axis, and Alcoholism

Academic journal article Alcohol Research: Current Reviews

Circadian Genes, the Stress Axis, and Alcoholism

Article excerpt

Alcohol abuse and dependence are estimated to affect 1 in 8 adults in the United States and several hundred million people worldwide (Grant et al. 2004). To define at-risk populations and develop better treatments, it is important to further identify the genetic and environmental factors that contribute to alcohol addiction. Recent evidence suggests that the body's internal system that helps control the daily rhythm of the body's activities (i.e., the circadian system), the body's stress response system, and the body's neurobiology of alcohol are extensively intertwined. This article explores some of these interactions.

The Circadian System and Alcohol's Effects on It

The circadian system--or the body's internal clock--is a naturally present regulatory system that helps the body maintain an approximately 24-hour cycle in biochemical, physiological, or behavioral processes, thereby allowing the organism to anticipate and prepare for regular environmental changes (i.e., the day--night cycle). For example, circadian rhythms maintain not only sleeping and feeding patterns but also physiological processes such as body temperature, brain-wave activity, hormone production, and cell regeneration. The circadian clockwork results from the interaction of specific clock genes, including genes known as Period (Per1, Per2, and Per3), Clock, Bmall, and Cryptochrome (Cry1 and Cry2), and others. (1) The activity of these genes is controlled by two tightly coupled transcriptional and translational feedback loops that sustain a near 24-hour periodicity of cellular activity. Expression of these clock genes, in turn, regulates the expression of other clock-controlled genes (Ko and Takahashi 2006).

In both humans and animal models, complex bidirectional relationships seem to exist between alcohol intake or exposure and circadian clock systems. The impact of the circadian system on alcohol use is shown by the fact that both preference for and consumption of alcohol are modulated by time of day, and studies found that genetic interactions link core circadian clock genes with alcohol drinking (Spanagel et al. 2005a, b). In addition, disruption of the normal circadian rhythm (i.e., circadian desynchronization) seems to increase the use of alcohol, as seen in frequent travelers and rotating-shift workers, possibly because it frequently activates the body's stress response (i.e., increases the allostatic load (2)) (Rosenwasser et al. 2010; Trinkoff and Storr 1998). At the same time, a strong relationship seems to exist between alcohol drinking and altered circadian functions. For example, alcohol intake can alter the following circadian responses:

* Circadian rhythms in blood pressure, core body temperature, and hormone release in humans (Danel et al. 2009; Devaney et al. 2003; Nakashita et al. 2009);

* Shifts in the normal circadian rhythm (i.e., circadian phase shifting) and in the free-running period (3) in mice (Prosser et al. 2008; Seggio et al. 2009);

* Return to a normal circadian rhythm after a disruption (i.e., circadian phase resetting) and nocturnal activity patterns in hamsters (Ruby et al. 2009; Seggio et al. 2007); and

* Rhythmicity in the activity of certain brain cells (i.e., proopiomelanocortin [POMC] (4)-producing neurons) in a brain region called the hypothalamus (which is involved in the body's stress system) in rats (Chen et al. 2004).

Even alcohol exposure before birth can interfere with circadian systems. Thus, prenatal ethanol exposure in rats can alter core body temperature and phase-shifting ability (Sakata-Haga et al. 2006); rhythmic activity of the pituitary gland and the adrenal gland, both of which are part of the body's stress response system (Taylor et al. 1982); the rhythmic release of the main stress hormone (i.e., corticosterone) (Handa et al. 2006); immune cell rhythms (Arjona et al. 2006); and circadian expression of POMC in the hypothalamus (Chen et al. …

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