Marijuana & Cytokine Actions on Rat Brain Mitogenesis

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DESCRIPTION (provided by applicant): A common result of chronic drug abuse is cognitive loss or dysfunction. In many of these cases no definitive neuropathology is associated with these deficits. A case in point is the cannabinoid drug, marijuana, whose use is most often associated with memory loss, following both acute and chronic intoxication. There is not, however, any definitive evidence of frank neuropathology associated with its use (cf. the drug "ecstasy" 3,4-MDMA). Recent evidence indicates that the mammalian brain (including humans) continues to produce new neurons into adulthood. Additionally, this process has been shown to be important in new learning and memory. This application proposes research which examines the effects of the delta-tetrahydrocannabinol (THC) on mitogenesis (cell proliferation), the first phase of neurogenesis, in the dentate gyrus (DG) of adult rats. These effects will also be studied in the context of their interaction with the proinflammatory cytokine interleukin-1beta (IL-1beta), which is released under a variety of infectious and stressful conditions. THC will be administered intraperitoneally both acutely and chronically in three doses. In addition, some of these animals will also be given IL-1beta chronically. Following these various drug treatments (or control treatments), all animals will be administered bromodeoxyuridine (BrdU) and sacrificed two hours later. The animals will be perfused and their brains removed and processed for BrdU-immunoreactivity. BrdU-labeled cells in the granule cell layer and hilus of the DG will be quantified using light microscopy. It is hypothesized that chronic, and possibly acute, THC will suppress DG mitogenesis and that the stress-related cytokine IL- 1beta will also have this effect. It is further hypothesized that the actions of the two compounds will be at least additive in suppressing DG mitogenesis.