Cocaine addiction in North America is a medical problem with profound social and financial cost. Understanding the neurobiological consequences of cocaine use is an important step in the development of appropriate treatments. An animal model is essential for evaluating the underlying neurobiology of drug abuse and for testing potentially therapeutic drugs. Cocaine self-administration in rats will be used to model these fundamental aspects of human drug taking. The development of human drug addiction is a process. We assert that increases in motivation to continue taking the drug is an important aspect of this process. Our goal has been to develop animal models of the addiction process, with a focus on increases in motivation assessed by a progressive ratio schedule. During the initial period of funding two very different self-administration procedures were identified which appear to model different mechanisms which contribute to a progressive motivational change. The phenomena which increase cocaine-reinforced break points are associated with different phases of the addiction process: (A) Induction phase: after very limited exposure animals demonstrate a progressive escalation in break points over the first two weeks of testing. This model shows the addiction process begins with virtually the first exposure to drug. (B) High intake phase: animals that have experienced high levels of daily cocaine show remarkably stable cocaine-reinforced break points. These can be further increased with extended round-the-clock access to cocaine for 10 days plus a drug deprivation of at least a week. This procedure models binge-abstinence cycles typical of human addicts. Experiments are proposed that will further characterize these phenomena and establish dose-response relationships and time course parameters. Cross-sensitization with amphetamine and methamphetamine will be assessed. Our hypothesis is that glutamate projections from the prefrontal cortex is important for the development (but not the expression) of sensitization and this will be addressed with pharmacological and lesion studies.
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