With these caveats, research on transgenic and knock-out animals is underway at an increasing rate. Once genetic mutant mice are generated, the next step is to identify phenotypic abnormalities. The field of drug abuse has been and will continue to be one important component of this research, because animal models of drug dependence are among the most accurate and straightforward to interpret with respect to clinical and physiological phenomena.
Progress is being made in identifying adaptations in signal transduction proteins that occur in specific brain regions following chronic exposure to drugs of abuse. One major challenge for future research is to identify and investigate a broader range of molecular and cellular targets of drugs of abuse than those currently under scrutiny. A second major challenge is to relate specific molecular and cellular adaptations to specific behavioral features of dependence, particularly drug reinforcement and motivational aspects of dependence. This will first require the development of rodent animal models that more accurately reflect the phenomenon of drug craving, which is a core clinical feature of addictive disorders. These animal models can then be used to study the functional relevance of adaptations in the cellular physiology of specific neuronal cell types; adaptations in specific signaling and structural proteins within these neurons; and ultimately, specific transcriptional, translational, and posttranslational mechanisms of the adaptive changes. The information gained may provide clues for the development of more effective medications and may aid in genetics research.
As described above, one of the major gaps in the neurobiology of drug dependence research is the integration of clinical phenomena with basic research. One area that needs attention is the further validation of current animal models (see Chapter 2) and, perhaps more importantly, the anchoring of the basic neurobiology in such models. Much of the current research focuses on the acute or semiacute administration of drugs, no validation of functional dependence (behavioral or physiological measures combined with biochemistry or molecular biology) is provided. Thus, large amounts of data are gathered on the effects of drug use, but how this is related to drug abuse and dependence is unclear.
Although models of drug self-administration and drug discrimination have provided an excellent basis for behavioral research (Chapter 2), models that can reliably reproduce the more complex behaviors of depen-