Marijuana is among the most widely abused drugs in the U.S. and its use is on the increase among the young. Among scientists and in the general population, marijuana is frequently viewed as a relatively innocuous drug with low addiction liability. One reason for this view is the paucity of withdrawal symptoms that occur upon abrupt cessation of chronic heavy use. One reason for such mild effects may be the long (36 hour) half life of delta 9-tetrahydrocannabinol (delta 9-THC), the main psychoactive constituent of marijuana. The brain may adapt during the long period of metabolism and excretion of the drug. In a recently completed study, we found that injections of the newly-developed cannabinoid antagonist SR14716A in rats chronically treated with delta 9-THC elicited a dramatic precipitated withdrawal syndrome characterized by extreme hyperactivity, disorganization of behavior, and certain very unusual symptoms such as rapid tremor-like medial-lateral movements of the forepaws. We propose to examine the behavioral, pharmacological and biochemical features of precipitated cannabinoid withdrawal. In the first series of experiments we address questions about the dose-requirements for the effect, the necessary durations of exposure, and the maximal syndrome that can be evoked following high doses and long exposures to delta 9-THC. In a second set of experiments we examine the anatomical sites that mediate precipitated cannabinoid withdrawal using three approaches: the distribution of the immediate-early gene c-for induced by precipitated withdrawal, the ability of discrete microinjections of the antagonist to produce the effect, and changes in extracellular levels of neurotransmitters (measured by in vivo microdialysis) that occur during precipitated withdrawal. In a third series of experiments we will investigate the effect of precipitated withdrawal on neuronal activity in the brain using electrophysiological techniques. These experiments may provide new information about the nature of cannabinoid withdrawal, and suggest possible treatments of the withdrawal symptoms that occur in humans following cessation of chronic heavy use of the drug.
