CB1 Receptor Action on the Developing Hippocampus

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DESCRIPTION (provided by applicant): Several adverse effects of marijuana (cannabis) use are recognized including those on central nervous system function. Among the most prominent effects of cannabis on neural function are deleterious influences on memory, which may be related to damage to the hippocampus. In the brain, the effects of cannabinoids are transduced by the CB1 receptor (CB1R). CB1Rs are highly expressed during development, couple with Gi/Go, inhibit neurotransmitter release, and hyperpolarize neurons. Whereas a considerable amount of information is known about cannabis and CB1R action in the mature nervous system, relatively little is known about effects on the developing brain. Increasing evidence suggests that suppression of neuronal activity during critical periods of brain growth will trigger neuronal apoptosis. Suggesting that the developing brain is also sensitive to effects of CB1R activation, we observe that acute cannabinoid exposure induces apoptosis in the developing, but not mature hippocampus. Based on these observations, we propose to test the hypotheses that (1) the developing hippocampus is especially sensitive to the effects of CB1R activation. (2) Cannabinoid toxicity during early development is due to inhibition of neuronal activity. To test these hypotheses we will perform in vivo and in vitro studies using contemporary neuroscience methods and CB1R knock-out mice. We anticipate that these studies will result in new insights into the potential effects of cannabinoid action on the developing brain.