Several lines of evidence indicate endocannabinoids act as retrograde messengers in the striatum, mediating the plasticity associated with marijuana and other drug addictions. As such, improving our understanding of the endocannabinoid system and its role in addiction warrants a high priority. It is further hypothesized that modulation of neuroplastic factors in the reward areas of the brain by cannabinoids is responsible for THC-induced reward and dependence. The new technology of RNA interference (RNAi), a potent post-transcriptional gene silencing phenomenon, will prove invaluable for studies of such neuronal systems. The use of this novel gene suppression technique provides an unprecedented level of control over the production of targeted gene products in specific regions of the mature brain, and thereby allows for the rapid, efficient and comprehensive evaluation of their activity in multiple behavioral addiction models. Specifically, we propose to explore the roles of several key mediators of neuronal plasticity in the production of THC-induced reward and withdrawal behaviors in mice through the use of interfering RNAs targeting these genes, delivered in vectors derived from Adeno Associated Virus. Because these are pilot studies, their scope is limited to targeting a few key molecules which seem likely to yield valuable information quickly. Vectors will be designed to target CREB, deltaFosB, BDNF, or PKA mRNAs, and stereotactically injected separately into the ventral tegmental area (VTA) and nucleus accumbens (NA) of subject mice. Once gene suppression is achieved, the ability of THC to induce rewarding effects in the treated animals will be tested by conditioned place preference (CPP), while dependence will be determined by measuring signs of precipitated withdrawal. Because THC is a partial agonist of cannabinoid receptors, initial studies will be repeated using the full agonist CP-55,940 for comparison. The information obtained from these studies will enhance our understanding of the molecular mechanisms responsible for THC-induced reward and dependence. Such information is essential to understanding the biology of the endocannabinoid system in regulating addiction, and will suggest additional targets for the development of treatments and therapies for drug addiction and addictive behaviors. These pilots also serve as a model for tracing key biochemical events in other types of dependency, and other kinds of behavior.
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