Stress and the Body's Response, Part 2

by National Institute of Health

(Page 3 of 6)

One likely explanation for the connection between stress and AOD use is that stress modifies the motivational and/or reinforcing effects2 of AODs at the neurobiological level. For example, stress increases the activity of the dopaminergic brain systems that are involved in motivation and reward and which also mediate AOD-induced rewarding effects. Accordingly, stress-induced changes in those systems could enhance the organism's responsiveness to the effects of AODs. Furthermore, when an organism is in a stressful situation, numerous biological systems are activated to help the organism cope with the stress. For example, the adrenal glands release epinephrine to prepare the organism for a "fight or flight" response, and various brain regions secrete pain-relieving chemicals. Similarly, stress possibly results in increased activity in the dopaminergic system in an attempt to counteract the negative emotional state associated with stress.

Animal studies have suggested that another neurotransmitter, serotonin, also may play a role in the relationship between stress and AOD use. For example, alcohol administration increases brain serotonin metabolism in animals. Furthermore, increases in serotonin levels and metabolism have been shown to decrease alcohol consumption in experimental animals. Studies in nonhuman primates found that animals with low brain serotonin activity are high consumers of alcohol. When these high alcohol-consuming animals were treated with an agent that prevents serotonin breakdown and thus prolongs serotonin's activity in the brain (a selective serotonin reuptake inhibitor [SSRI]), their alcohol consumption declined substantially. Clinical trials investigating the use of SSRIs in humans, however, have generated mixed results regarding the ability of those agents to decrease alcohol consumption.

In addition, animal studies have indicated that the brain's serotonin systems also affect the brain regions that mediate another stress-related reaction, the fear response. Consistent with this observation, many SSRIs have demonstrated powerful activity in the treatment of anxiety disorders in humans in addition to their antidepressant activity. This association of the serotonin system with both consummatory behaviors and anxiety states further supports the notion that a neurobiological connection exists between stress and AOD use and abuse.

Animal Models of the Relationship Between Stress and Relapse

Numerous studies using various animal models have examined the relationship between stress and the initiation or the reinstatement of alcohol use after a period of abstinence. These studies are summarized in the following sections.

Stress and the Initiation of Alcohol Use

Animal studies have demonstrated that exposure to both acute and repeated stress can increase an animal's potential for initiating AOD self-administration as well as modify the amount and frequency of established AOD selfadministration. However, this relationship appears to depend on the timing of the exposure to a stressor and of the AOD exposure. For acute stress to induce AOD administration, the stressful event and the AOD exposure must occur within a short interval.

For example, in experiments in which animals were exposed to acute stress by restraining them for a short period of time, AOD self-administration was facilitated only if the stressful situation preceded the AOD exposure by no more than 30 minutes. When the animals were exposed to stress repeatedly or for prolonged periods, however, the interval between the end of the stressful situation and the AOD exposure did not appear to influence AOD self-administration. Thus, in those instances the animals showed increased AOD self-administration regardless of whether the stressful experiences continued up to the AOD-use assessment or had ended weeks earlier. These observations indicate that repeated stress can induce long-lasting modifications in neural pathways, resulting in a drug-prone state that is independent of the actual presence of the stressor.

Although stressors that have a physical component, such as a mild electric shock to the feet or a pinch in the tail, can lead to increased AOD self-administration, such physical manipulations do not appear to be required for mediating stress effects. In fact, psychological stress alone can also increase drug self-administration. For example, rats that witnessed another animal receiving an electric shock exhibited increased self-administration of cocaine. Similarly, enhanced AOD self-administration occurred in studies in which animals were exposed to stress in the form of social aggression by being placed in an unfamiliar group of animals while being protected from actual physical attacks by a screen grid.

Stress and the Reinstatement of Alcohol Use

Stressful experiences also can contribute to the reinstatement of AOD use after a period of abstinence in animals with a history of AOD self-administration. For example, studies in rats found that a single stressful experience, such as a one-time electrical shock to the feet, induced resumption of drug use in animals that had been previously taught to self-administer cocaine or heroin. This stress-induced reinstatement of AOD use is a well-documented phenomenon. In fact, exposure to stress is the most powerful and reliable experimental manipulation used to induce reinstatement of AOD use.

Animal models of the relationship between stress and alcohol relapse have employed not only animals with a history of alcohol self-administration that had undergone a prolonged period of abstinence but also animals with a history of alcohol dependence that were deprived of alcohol. Studies found that both alcohol-dependent and non-alcoholdependent animals will increase their response for alcohol (compared to baselike levels) following a period of imposed deprivation.

Researchers have used such an alcohol deprivation model in dependent rats to investigate the effects of two medications used to treat alcoholism in humans, naltrexone and acamprosate. Both of these agents interfere with the actions of the neurotransmitters involved in mediating stress and the reinforcing effects of alcohol. Thus, naltrexone blocks the actions of neurotransmitters called endogenous opioids, and acamprosate likely interferes with the function of the neurotransmitter glutamate. In alcohol deprivation studies in rats, both agents prevented the increase in alcohol selfadministration normally observed in animals that experience stress as a result of a period of forced abstinence. Similarly, opioid antagonists prevented the increase in alcohol consumption observed in animals exposed to other types of stress.

Stress in humans often leads to craving, and craving, in turn, frequently results in relapse. Thus, one can reasonably assume that opiate antagonists - which are considered anticraving medications - could reduce stress-induced craving and thereby decrease the risk of a stress-induced relapse. Although human studies have confirmed that naltrexone and another opiate antagonist, nalmefene, are both effective in preventing relapse in abstinent alcoholics, the effects of opiate antagonists on stress-induced relapse have not yet been investigated specifically in humans.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.