Figure 2

Alcohol and Stress

Interactions between stress and alcohol have been postulated based on experimental and anecdotal evidence. However, the relationship between stress and alcohol intake is complex, and is not completely understood. It has been hypothesized for many years that the ability of alcohol to reduce stress underlies its ability to serve as a reinforcer (Pohorecky, 1981). Stress is a common human experience yet it has very subjective meaning.

Clearly what "stresses" an individual is highly dependent upon personal history, genetic makeup and current physiological status. Perhaps this is why it is so difficult to clearly implicate stress and the effects of stress as having a causal role in excessive alcohol consumption. One approach to understanding the interaction between stressful events and alcohol consumption is to demarcate acute and chronic stress, and view chronic stress as the platform to dysfunctional outcomes in response to acute stress.

From this framework, an acute stressful event will often synergize with a chronic stressful state, producing an adverse outcome that would otherwise be benign. The link to excessive alcohol consumption may be that chronic alcohol consumption itself produces a state of chronic stress.

Chronic stress places a strain on physiological systems that maintain homeostasis and can lead to a deterioration of these systems as well as forcing a new "operating range" of these physiological systems. The term "allostasis was first coined to define the operating range and ability to increase or decrease vital functions to a new steady state in the face of stress (Sterling and Eyer, 1988). Later, the term allostatic load was introduced to represent the strain on the body produced by repeated ups and downs of physiological response and the elevated activity of physiological systems under challenge (McEwen and Stellar, 1993).

Interestingly, in their review article "Stress and the Individual" McEwen and Stellar referred to the well-entrenched hypothesis of alcohol consumption to relive stress with the following quote: "An example of allostatic load linked to behavioral processes and with a clear-cut effect of health is the reciprocal introductionrelationship between stress and alcohol consumption" (McEwen and Stellar, 1993).

Indeed, there is clinical evidence indicates a high degree of co-occurrence of anxiety and alcohol dependence (see Kushner et al., 1990, Crum et al, 1995). Two mechanisms are likely responsible for this comorbidity. First, excessive ethanol intake may be due to the anxiolytic properties of ethanol alleviating a constant "basal" state of anxiety in some individuals. Second, abstinence subsequent to excessive and prolonged consumption of alcoholic beverages gives rise to dysphoric effects, including anxiety, which may be relieved by ethanol consumption.

Anxiety appears to correlate with the relapse rate in studies of recovering alcoholics (Brown et al. 1995) and voluntary ethanol intake in both non-human primates (reviewed in Higley and Linnoila 1997) and rats (Colombo et al. 1995; Spanagel et al. 1995, Stewart et al. 1993). This species-independent association between ethanol withdrawal and anxiety reflects the conservation of the neural mechanisms responsible for anxiety-related behaviors (reviewed in Davis et al. 1994; Aggleton 1993). However, stress reduction is not always seen after acute alcohol intake in humans (Wand et al. 1998), and thus it is not simply the case that people drink to relieve stress. Indeed the exact relationship between stress and alcohol abuse is still being characterized (Wand, 2000; Rivier, 2000). However, it is clear that alcohol does have anxiolytic effects under some conditions (Kushner et al., 1990), and that there are clear examples of stress/alcohol interactions (Wand, 2000). These interactions are complex and, at times, appear contradictory.

While we most often think of the stress-alcohol relationship in terms of environmental factors that lead to drinking, this relationship is likely to be strongly influenced by other factors. One influence on drinking is the genetic predisposition to alcoholism that has been documented in a number of studies (Reich et al. 1999, Cloninger et al. 1981, Cotton 1979, Goodwin et al. 1973, Heath et al. 1997). It is possible that some of this predisposition arises from inherited traits that affect responses to stress. Indeed, work with animal models such as the P/NP and SP/SNP rats suggests that inherited anxiety traits may contribute to the heritability of high alcohol intake (Stewart et al., 1993, Colombo et al, 1995). However, this is a complex issue and while some studies have supported the idea that individuals who are family history positive for alcoholism show altered stress reduction when given alcohol (Levenson et al. 1987, Finn et al. 1990), there are conflicting findings in the literature (c.f. Sayette et al. 1994). It is thus important to determine what genetic factors contribute to alcohol intake as well as stress-alcohol interactions.

In this INIA we take several approaches to understanding stress, anxiety and alcohol abuse. These include characterizing alcohol effects on brain circuitry involved in responses to stress, and neuroadaptive changes in this circuitry in response to chronic alcohol exposur. This analysis is extended to cellular, synaptic and molecular mechanisms involved in alcohol/stress interactions. Genetic approaches include searching for QTLs for alcohol intake and withdrawal, examining SNPs from anxious alcoholics, and examining the effects of specific genetic mutations and gene knockouts on stress-alcohol interactions.

The goal of this INIA consortium is to conduct research that will explore facets of these interactions at all levels from molecules to behavior. It is our overarching INIA Hypothesis that stress and stress-induced anxiety contribute to excessive ethanol consumption by interacting with (1) Neuroadaptive responses to ethanol and (2) Genetic factors that influence stress and drinking.

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