New dimensions in human laboratory models of addiction

Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity. Impulsivity can be defined behaviorally as a tendency toward rapid, unintended reactions to internal and external stimuli without regard for the negative consequences of these reactions. Compulsivity can be defined as an element of behavior that results in perseveration in responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations and is associated with exaggerated response inhibition. From a psychiatric perspective, impulsivity can be characterized by an increasing sense of tension or arousal before committing an impulsive act, and pleasure, gratification or relief at the time of committing the act. Compulsivity can be characterized by anxiety and stress before committing a compulsive repetitive behavior and relief from the stress by performing the compulsive behavior (American Psychiatric Association 1994). Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle composed of three stages: preoccupation/anticipation, binge/intoxication and withdrawal/negative affect (Table 1). Impulsivity often dominates at the early stages and compulsivity dominates at terminal stages. As an individual moves from impulsivity to compulsivity, a shift occurs, from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob 2004). These three stages are conceptualized as interacting with each other, with the negative reinforcement component becoming more intense, and ultimately leading to the pathological state known as addiction (Koob & Le Moal 1997). The addiction cycle construct provides an excellent framework by which to interpret animal models for studying the etiology of the addiction process, neurobiology of addiction and treatment of addiction. Importantly, human laboratory studies—the subject of this special issue of Addiction Biology—can provide a powerful means of exploring treatment targets for specific components of the addiction cycle independent of expensive double-blind, placebo-controlled trials. Animal models for addiction are some of the most robust in neurobiology and have provided a heuristic framework not only for understanding the basic neurobiology of the actions of drugs of abuse, but also for providing a pipeline of potential targets for addiction treatment. While no animal model of addiction fully emulates the human condition, the models do permit investigation of the specific elements of the addiction process. Such elements can be defined by models of actual symptoms of addiction within different stages of the addiction cycle. Different animal models for the study of the neurobiology of addiction can be superimposed on the same three stages of the addiction cycle described above. Animal models for the binge/intoxication stage of the addiction cycle incorporate the construct of immediate, positive drug reinforcement. Animal models of drugs as reinforcers are extensive and well-validated. Drugs of abuse have powerful reinforcing properties, and animals and humans readily self-administer drugs in the nondependent state. Animals will perform many different tasks and procedures to obtain the drugs, even in the non-dependent state. Drugs that are self-administered by animals correspond well with those that have high abuse potential in humans, and drug self-administration is considered an animal model that is predictive of abuse potential (Collins et al. 1984). Two other animal models have been used extensively to measure drug reward indirectly: conditioned place preference and brain stimulation reward (Table 1). Conditioned place preference is a nonoperant procedure for assessing the reinforcing efficacy of drugs using a classical or Pavlovian conditioning procedure. Animals typically exhibit a conditioned place preference for an environment associated with drugs that are self-administered by humans and avoid environments that induce aversive states (i.e. conditioned place aversion). Lowering of brain stimulation reward thresholds also is a reliable measure of drug reward. Drugs of abuse decrease thresholds for brain stimulation reward, and good correspondence exists between the ability of drugs to decrease brain reward thresholds and their abuse potential (Kornetsky & Bain 1990). Animal models are specifically designed to address compulsivity-like elements of the binge/intoxication stage and the increased motivation to seek drugs. Such measures include binge drug-taking (Tornatzky & Miczek 2000), increased drug intake produced by extended access to drugs (Ahmed & Koob 1998) and drug-seeking despite negative or aversive consequences (DerocheGamonet, Belin & Piazza 2004; Vanderschuren & Everitt 2004) (Table 1). There are compelling studies showing drug-taking in the presence of aversive consequences in animals with extended access to the drug. Rats with extended access to cocaine do not suppress drug-seeking in the presence of an aversive conditioned stimulus, which has face validity for the DSM-IV criteria of ‘continued substance use despite knowledge of having a GUEST EDITORIAL Addiction Biology