Animal Models of Addiction

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Most of the animal models discussed in this section have predictive validity for certain components of the addiction cycle and generate reliable effects in animals. Achieving predictive validity is more problematic for constructs such as craving because of the nebulous conceptualizations and various definitions of craving in humans. Virtually all of the measures described here for animal models of addiction have demonstrated reliability, consistency, stability of the measures, small within-subject and between-subject variability, and reproducibility of the phenomena.

Much remains to be explored about the face validity and predictive validity of unconditioned positive and negative motivational states, particularly the conditioned positive and negative motivational states associated with drug use and withdrawal. Determining the specific changes in the central nervous system associated with these models will provide further insights into both drug dependence and psychopathologies associated with anxiety and affective disorders. Animal models of addiction provide the foundation to begin such studies.

Keywords

animal model; face validity; predictive validity; reinforcement; motivation; construct validity; validation; addiction; reliability; self-administration

The definition of drug addiction to be used in this book draws on several different meanings of drug addiction (see What is Addiction?):

  1. Compulsion to seek and take the drug,
  2. Loss of control in limiting intake, and
  3. Emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented.

Much of the recent progress in understanding the mechanisms of addiction has derived from the study of animal models of addiction that use specific drugs, such as opiates, cocaine, and alcohol. No single animal model of addiction fully emulates the human condition, but various models permit researchers to investigate specific elements of the addiction process. Some models evaluate psychological constructs, such as positive and negative reinforcement. Other models evaluate different stages of the addiction cycle, and still others evaluate actual symptoms of addiction from a psychiatric perspective. For the purposes of this section, animal models will be categorized based on the three stages of the addiction cycle and the actual psychiatric symptoms of addiction.

Drug addiction can be heuristically characterized as a cycle that includes three stages: (1) preoccupation/anticipation, (2) binge/intoxication, and (3) withdrawal/negative affect. A primary focus of animal studies has been on the central nervous system mechanisms and synaptic sites where drugs of abuse initially act to produce their positive reinforcing effects, but newer, more refined animal models can assess the negative reinforcing effects of dependence and how the central nervous system adapts to drug use.

The constructs of reinforcement and motivation are crucial parts of all animal models of addiction. The process by which a stimulus increases the probability of a response is termed reinforcement. A reinforcer, which can be a drug, is any event that increases the probability of a response. This definition can also apply to the definition of reward, and the two words are often used interchangeably. However, reward often connotes some additional emotional value, such as pleasure. Multiple powerful sources of reinforcement have been identified during the course of drug addiction research. Positive reinforcement is defined as the presentation of an event that increases the probability of a response. An example is drug seeking in a nondependent individual. Negative reinforcement occurs when the removal of an aversive event increases the probability of a response. One example is a person who self-administers a drug to provide relief from the aversive aspects of drug abstinence or withdrawal.

These sources of reinforcement provide the motivation to compulsively use drugs, with a concomitant loss of control over intake (Wikler, 1973). Motivation has several definitions. Donald Hebb defined it as “stimulation that arouses activity of a particular kind” (Hebb, 1949). C.P. Richter stated that “spontaneous activity arises from certain underlying physiological origins and such ‘internal’ drives are reflected in the amount of general activity” (Richter, 1927). A behavioristic view put forth by Kling and Riggs is that motivation is “the property of energizing of behavior that is proportional to the amount and quality of the reinforcer” (Kling and Riggs, 1971). Dalbir Bindra defined it as a “rough label for the relatively persisting states that make an animal initiate and maintain actions leading to particular outcomes or goals” and went further by defining it from a more neurobehavioral perspective: “[a] set of neural processes that promote actions in relation to a particular class of environmental objects” (Bindra, 1976).

As noted above, the primary pharmacological effect of a drug can produce a direct effect through either positive or negative reinforcement. The secondary pharmacological effects of a drug also can have motivating properties. For example, conditioned positive reinforcement involves the pairing of a previously neutral stimulus, perhaps a particular room or a favorite bar, with the acute positive reinforcing effects of a drug. Conditioned negative reinforcement involves the pairing of a previously neutral stimulus with the aversive stimulus effects of withdrawal or abstinence (Table 3.1).

One approach to the development of animal models that has gained wide acceptance in the research community is that they should have construct validity or predictive validity, in which the model mimics specific signs or symptoms associated with a particular psychopathological condition. Animal models of a complete syndrome of a human psychiatric disorder are unlikely to be possible either conceptually or practically. Certain areas of the human condition are obviously difficult to model in animals, like kleptomania, child abuse, etc. From a practical standpoint, psychiatric disorders are based on a classification of diseases that is complex and constantly evolving. Such disorders often have multiple subtypes and diverse etiologies, and many of them are in fact constellations of many different disorders. Any animal model that attempts to reproduce entire syndromes of the human condition would require multiple endpoints, making the practical study of the underlying mechanisms very difficult.

Under such a framework of mimicking only very precise signs or symptoms of a psychopathological condition, specific “observables” (symptoms that one can observe) that have been identified in addiction provide a focus for animal studies. The reliance of animal models on a given observable also eliminates a fundamental problem associated with animal models of human psychopathology – the frustration of attempting to provide complete validation of an entire syndrome. More definitive information related to a specific domain of addiction can be generated, thus increasing the confidence of cross-species validity. This framework also leads to a more pragmatic approach to the study of the neurobiological mechanisms of the behavior in question.

TABLE 3.1

Relationship of Addiction Components and Behavioral Constructs

Addictive Component

Behavioral Construct

Pleasure

Positive reinforcement

Self-medication

Negative reinforcement

Habit

Conditioned positive reinforcement

Habit

Conditioned negative reinforcement

In the present section, these observables are organized under the framework of the binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving) stages of the addiction cycle. Further on in the section, however, these observables are linked to the actual criteria for addiction in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV), and human clinical laboratory models of addiction. The particular behavioral parameter being assessed in an animal model may or may not be a particular symptom of the disorder, but it still must be defined objectively and observed reliably. The behavior being analyzed may actually be found in both pathological and nonpathological states but still have predictive validity. A good example of such a situation is the widespread, and sometimes misguided, use of drug reinforcement or reward as a definitive animal model of addiction. Drug reinforcement does not necessarily lead to addiction. Take, for instance, a social drinker who does not develop alcoholism. Nonetheless, drug self-administration by animals has significant predictive validity for the binge/intoxication stage of addiction, and one may confidently state that drug addiction indeed cannot happen without drug reinforcement.

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