Animal Models of the Binge/Intoxication Stage of the Addiction Cycle

Summary of Animal Models of the Binge/Intoxication Stage

The experimental paradigms outlined above have proven reliability and predictive validity in their ability to understand the neurobiological basis of the acute reinforcing effects of drugs of abuse and compulsive drug seeking associated with the binge/intoxication stage of the addiction cycle. However, one could reasonably argue that drug addiction also involves counteradaptive mechanisms that go far beyond solely the acute reinforcing effects. Nonetheless, understanding the neurobiological mechanisms of the positive reinforcing effects of drugs of abuse can provide a framework for understanding specific changes in a drug’s motivational effects as addiction develops. One strength of the models outlined above is that any of the operant measures can be used in within-subjects designs, meaning that the same animals can be subjected to different manipulations, thus limiting the number of animals required for research. Once an animal is trained to, say, press a lever, full dose-effect functions can be generated for different drugs, and the animal can be tested for weeks or even months. Once an animal is tested with a particular experimental drug, additional pharmacological manipulations can be done with standard reference compounds, using the same animals, to validate the effects. A rich literature on the experimental analysis of behavior is available to explore the actions of various drugs, which can be used to develop additional experimental protocols that attempt to alter drug reinforcement by modifying the history and contingencies of reinforcement.

The advantage of the ICSS paradigm as a model of the effects of drugs on motivation and reward is that the threshold provided by ICSS is easily quantifiable. Such threshold estimations are very stable over long periods of time, up to several months (Stellar and Stellar, 1985). Another considerable advantage of the ICSS technique is its high reliability of predicting the abuse liability of drugs. A false-positive result has never been obtained with the discrete trials threshold procedure.

Place conditioning has several advantages as a model for evaluating drugs of abuse: it is highly sensitive to even very low doses of drugs; it can be used to study both the positive and negative reinforcing effects of drugs; and it tests drug reward under drug-free conditions. It also allows for the precise control of interactions between environmental cues and drug administration.

Animal models associated with responding in the face of punishment and the progressive-ratio schedule have both face and construct validity. Numerous studies in humans have found that people who meet the criteria for substance dependence will work hard to obtain drugs and show increased motivation for drug taking. As addiction develops, an individual’s behavioral repertoire narrows toward drug seeking and taking. Progressive-ratio studies in humans have found similar patterns of responding to those in the animal models. Clearly, responding in the face of punishment and progressive-ratio responding in rodents show individual differences that are reminiscent of the individual differences found in the human population. From the perspective of construct validity, responding in the face of punishment and progressive-ratio paradigms predict a key role for midbrain dopamine systems in the reinforcing effects of cocaine. Second-order schedules of reinforcement with a well-established cocaine “habit” have revealed a key role for dorsal striatal mechanisms in the increased motivation to work for cocaine.

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