Neurobiological and Neurobehavioral Mechanisms of Chronic Alcohol Drinking Neurobiological and Neurobehavioral Mechanisms of Chronic Alcohol Drinking Alcoholism comprises a set of complex behaviors seeking behaviors, have been developed. These in which an individual becomes increasingly models, which remain an integral part of the preoccupied with obtaining alcohol. These study of alcoholism, include animals that pref- behaviors ultimately lead to a loss of control over erentially drink solutions containing alcohol, consumption of the drug and to the development animals that self-administer alcohol during of tolerance, dependence, and impaired social and withdrawal, animals with a history of dependence occupational functioning. that self-administer alcohol, and animals that self- administer alcohol after a period of abstinence Although valuable information regarding toler- from the drug. Genetic models for alcoholism ance and dependence has been, and continues to also exist and include animals that have been bred be, gathered through human studies, much of the selectively for high alcohol consumption. Studies detailed understanding of the impact of exposure using such models are uncovering the systemic, to alcohol on behavior and on the biological cellular, and molecular neurobiological mech- mechanisms underlying those behaviors has been anisms that appear to contribute to chronic obtained through the use of animal models for alcohol consumption. The challenge of current alcoholism and a variety of in vitro, or cellular, and future studies is to understand which specific systems. Through the use of cellular systems and cellular and subcellular systems undergo mole- animal models, researchers can control the genetic cular changes to influence tolerance and depen- background and experimental conditions under dence in motivational systems that lead to which a specific alcohol-related behavior or chronic drinking. neurochemical change occurs. Reinforcement and Reward in It is difficult, if not impossible, to obtain an Chronic Drinking animal model that by itself incorporates all of the signs, symptoms, and behaviors associated with Because alcoholism centers on compulsive, alcoholism. However, several animal models often excessive, use of alcohol, the concept of of chronic drinking reflecting the different reinforcement or motivation is a crucial part of components of alcoholism, including alcohol- this syndrome. A reinforcer is defined as any Tolerance and Dependence Tolerance is present when, following prolonged exposure Alcohol dependence is defined as the manifestation of to alcohol, the brain becomes less sensitive to the acute either physical withdrawal symptoms, such as tremors actions of alcohol. For example, research shows that and seizures, after abrupt cessation of alcohol intake or larger doses of alcohol are needed to produce an alcohol- psychological symptoms, such as a negative emotional specific effect, such as sedation, in animals that have state after intake ends. The physical and psychological been given alcohol for several days or weeks compared symptoms that occur following termination of alcohol with animals given the drug the first time. Tolerance intake are collectively referred to as the alcohol with- appears to occur through adaptations at the cellular and drawal syndrome. Alcohol’s ability to induce pleasurable subcellular levels as the brain attempts to overcome the feelings, reduce tension and anxiety, and ameliorate the acute effects of alcohol intake; with prolonged alcohol symptoms of withdrawal make it a powerful and abuse, these adaptations often lead to permanent “attractive” drug. adverse changes in the structure and function of neurons. 107 Chapter 2: Alcohol and the Brain: Neuroscience and Neurobehavior event that increases the probability of a response. However, alcohol may, under certain conditions, This explanation also can be used to define serve as a deterrent to the seeking or obtaining of reward; in fact, “reinforcement” and “reward” more alcohol. Research shows that alcohol can be frequently are used interchangeably. However, aversive at high doses and, in animals, can cause reward often also connotes an additional both place avoidance, in which animals avoid an emotional value, such as pleasure (White and environment where they have previously received Wolf 1991). Many sources of reinforcement, alcohol, and taste avoidance, in which animals such as pleasure, mood elevation, and removal avoid a taste previously paired with alcohol of negative emotional states, contribute to ingestion (Cunningham et al. 1992). Alcohol- compulsive alcohol use during the course of dependent individuals have what is known as alcoholism. elevated aversion thresholds; that is, they can consume higher levels of alcohol than non- The primary pharmacologic action of alcohol dependent individuals before they stop drinking produces a direct effect through positive or or avoid alcohol. This elevated aversion threshold negative reinforcement. Positive reinforcement may contribute to excessive drinking among refers to a pleasurable or otherwise positive event dependent persons. that increases the likelihood that additional alcohol will be sought. Alcohol itself can serve By applying these concepts, researchers can as a powerful positive reinforcing agent through explore the neurobiological bases for the acute its ability to induce pleasurable or mood-elevating positive reinforcing effects of alcohol, the negative feelings (so-called euphoric or euphorogenic reinforcing effects imparted by the dependent effects). In contrast, negative reinforcement state, and the conditioned reinforcing effects describes an adverse event or situation that also associated with protracted abstinence and relapse will lead the individual to obtain more alcohol. (Koob et al. 1993). Examples of negative reinforcement include situations in which an individual or animal self- Insights Into Features of Alcoholism medicates in an attempt to overcome an existing From Animal Models aversive state (depression or anxiety) or to treat a drug-generated aversive state (alcohol-related The importance of animal studies lies in their withdrawal) (Wikler 1973). Both the positive potential for providing insight into alcoholism and negative types of reinforcement encourage in humans. Although not all the factors alcohol-seeking behavior and appear to contribute contributing to alcoholism, including the genes to chronic drinking, alcohol dependence, and a responsible for alcohol-related behaviors, have return or relapse to drinking among persons been discovered, animal models of alcoholism are recovering from alcoholism. proving to be instrumental in identifying genetic and biological factors that confer predisposition The secondary pharmacologic effects of alcohol to alcoholism. Such models enable researchers also can have powerful motivating properties. to perform controlled analyses of genetically and Conditioned reinforcement—when an individual environmentally influenced traits and behaviors learns to associate the reinforcing effects of that resemble certain aspects of human alcohol- alcohol with a previously neutral event or ism, such as alcohol consumption and preference, stimulus—results in secondary positive reinforc- innate sensitivity or tolerance to alcohol, and ing effects. In practical terms, a person entering metabolic rate of alcohol elimination. Much a familiar bar or pub can experience positive of the study of genetics and alcohol-related feelings similar to those induced by consumption behaviors or traits is conducted through the of alcohol. Secondary reinforcing effects can be use of selectively bred animals, such as alcohol- negative or positive; someone can also learn to preferring and alcohol-nonpreferring rats and associate particular stimuli with unpleasant mice. Additional studies use animals that are aspects of abstinence, such as withdrawal trained or conditioned to choose alcohol over symptoms. water or other usually preferable solutions. 108 Neurobiological and Neurobehavioral Mechanisms of Chronic Alcohol Drinking Animal Models for Alcoholism Validated animal models exist for many of the components alcohol, unless they have been bred for a specific genetic of alcoholism. Validation of an animal model focuses predisposition for alcohol preference. Thus, the results on three factors: face validity, reliability, and predictive of alcohol preference tests provide researchers with validity (predictability). Face validity is how similar, at least information regarding an innate preference or aversion to superficially, a behavioral effect in an animal is to that in the pharmacologic effects of alcohol or the extent to which humans. Face validity is a valuable starting point in an animal’s initial aversion to the taste or smell of alcohol alcohol research studies using animal models but is may be overcome to the point where the animal seeks out often difficult to truly achieve. Reliability refers to the the alcohol solution. However, this type of task involves consistency and stability of the variable of interest in little work or effort to obtain alcohol. the animal. Predictive validity refers to how closely and In contrast, in operant behavior models of self- accurately the animal’s condition mimics or predicts the administration, access to alcohol requires a specific condition in humans, based on the behavior of the animal learned behavioral response (or series of responses), model. such as pressing a lever or running a