Research into the effects of cannabinoid on brain function has become of increased relevance with respect to potential clinical uses of marijuana, for example: appetite enhancement in AIDS patients, and relief of nausea associated with chemotherapy. In addition, widespread """"""""recreational"""""""" use/abuse of marijuana also necessitates better understanding of cannabinoid's effects, especially those on cognitive function. The overarching tenet of this proposal pertains to the comparison of systemic with local cannabinoid administration to reveal global, as opposed to regional, mechanisms of cannabinoid, and cannabinoid receptor involvement in memory formation. This will be achieved by combining hippocampal ensemble recordings with pharmacological manipulation in two distinct behavioral paradigms:(DNMS) and open-field water maze. Both tasks require on-line processing of multimodal information during working to short-term memory processing (DNMS task) and short-term to long-term memory processing (water maze). To this end, electrode-recording arrays implanted into the dentate gyrus/CA3 should reveal differentiation of functions in processes of encoding, consolidation, and memory recall. ? ? The initiation of a collaborative effort between Wake Forest University Health Sciences and the University of Aberdeen, has aided the technical refinement of site-directed infusion targeting the same brain region that is under electrophysiological investigation. Results from agonist infusions will confirm and extend previous systemic studies, such that learning-related alterations can be pinpointed to the hippocampal cannabinoid system. While initial work using acute administration of cannabinoid receptor agonists and antagonists will establish the principal involvement of the cannabinoid system in memory formation, a more meaningful elucidation of consequences of frequent medicinal or recreational use will be provided by studies of chronic (28 day) cannabinoid exposure. This will permit a better physiological, pharmacological, and psychological understanding of mechanisms of tolerance. The strength of this approach is consistency between dose, vehicle and route of administration for the acute and chronic, systemic and local infusion studies, paired with established behavioral paradigms that are well suited to dissecting various stages of memory processing. ? ?
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