This is a request for a MERIT extension of Grant R37 DA004294. Considerable progress has been made over the past grant period, resulting in the publication or submission of 42 papers, including 31 primary research papers. A detailed description of both published work and work in progress is provided. The focus over the past grant period has been on how the circumstances surrounding drug administration modulate both the behavioral and neurobiological actions of drugs of abuse, and their ability to induce forms of drug experience-dependent plasticity thought to be important in the transition to addition. We have shown, for example, that both the envionmental context in which drugs are experienced, and the rate at which drugs reach the brain, powerfully modulate acute drug effects, their ability to produce psychomotor sensitization, and the cells and circuits engaged by drugs (as indicated by the specific cells and circuits that show drug- induced immmediate early gene expression). Many of these studies have emphasized the phenomenon of psychomotor sensitization. However, it has been hypothesized that the transition to addiction is due in large part to the interaction of incentive sensitization, which leads to pathological incentive motivation for drugs, and persistent cognitive deficits in decision-making and judgment due to frontal cortical dysfunction. Thus, in the future we propose to focus on these two issues. In the past grant period we developed a procedure based on the propensity of animals to approach cues associated with rewards (sign tracking), and have applied it for the first time to the study of cocaine. This approach will allow us to characerize the conditions that lead to the attribution of incentive salience to drug-associated cues, and how this changes as a consequence of past drug experience (i.e., incentive sensitization). We have also developed a procedure that reveals, for the first time in an animal model, persistent cognitive deficits as a consequence of cocaine self-administration experience. Thus, we propose studies to explore the conditions under which past cocaine experience alters both incentive motivation for drug, and cognitive function. We believe this two-pronged approach will yield important new insights into the psychology and neurobiology of addiction.
Showing the most recent 10 out of 74 publications
