The psychotropic substance, cannabis (marijuana), is becoming increasingly accepted, for both medicinal and recreational purposes. Cannabis is used predominantly by young adults of childbearing ages and since warnings against its use during pregnancy have not been forthcoming, it is frequently used/abused during these critical periods. It has in fact been estimated that more than 10% of pregnancies in the United States and Europe are affected by maternal cannabis use. Although both human clinical observations and animal studies have demonstrated that prenatal and/or neonatal exposure to cannabis produces a range of neurocognitive and neurobehavioral deficits, relatively little is known of the molecular mechanisms involved, and the extent of the central nervous system (CNS) damage produced. The proposed studies will combine behavioral and neuroanatomical analyses of the neurobiological consequences of prenatal and early postnatal cannabis (CB) exposure, to test the global hypothesis that a critical mechanism underlying cannabis neurotoxicity to the developing CNS is the cannabis receptor-mediated triggering of the intrinsic apoptosis pathway, leading to cell death within CNS regions corresponding to many of the previously demonstrated cannabis-related behavioral/cognitive/motor deficits, i.e., prefrontal cortex, hippocampus, and cerebellum. For these studies, ?9-tetrahydrocannabinol (?9THC), the primary psychoactive component of marijuana, will be administered during gestation or in the early neonatal period, to wild-type mice, and to genetically engineered mice, lacking the pro-apoptotic bax gene. We will then conduct behavioral tests chosen to reveal functional deficits specific to these CNS regions, and will determine whether loss of Bax attenuates these deficits. We will then perform stereological counts of neurons in prefrontal cortex, hippocampus, and cerebellum, regions critical to the behavioral tasks chosen, to determine whether ?9THC-induced neuronal loss contributes to the behavioral deficits, and whether loss of Bax mitigates this loss. Individual identities will be retained so that behavioral and neuroanatomical data may be correlated. We hypothesize that loss of this primary apoptosis effector will significantly improve performance in behavioral/cognitive/motor tasks, accompanied by blocking or blunting ?9THC-mediated neuronal death. This project will be the first to investigate apoptotic neuronal loss as a consequence of developmental THC exposure, and as an antecedent to THC-mediated behavioral/cognitive deficits; and will also be the first to use gene-deletion technologies to define critical mechanisms underlying the harmful effects of ?9THC on the developing brain.
The psychotropic substance, cannabis (marijuana), is becoming increasingly accepted both for medicinal purposes, as well as for recreational use, and is generally viewed as a ?harmless? drug. Cannabis is used predominantly by young adults of childbearing ages, and it has been estimated that more than 10% of pregnancies in the United States and Europe are affected by maternal cannabis use. Although both human clinical observations and animals studies have found that prenatal and/or neonatal exposure to cannabis produces a wide range of neurocognitive and neurobehavioral deficits, relatively little is known of the molecular mechanisms involved, and the extent of the CNS damage produced.
