DESCRIPTION (provided by applicant): Recent surveys have indicated that the rate of use of marijuana among the general population has increased to as high as 7%. Moreover, marijuana has now been legalized in 18 states and the District of Columbia for medical purposes, which has contributed to the notion that this illicit drug may pose the least health-related risks. This has not been verified, however, and there is a real need to understand all of the biomedical consequences of cannabinoid use and abuse. The present application brings together a multidisciplinary team of investigators to examine whether the presence of ovarian hormones and acute or chronic 9- tetrahydrocannabinol ( 9-THC) administration reduces memory deficits in females. Chronic administration of 9-THC is of particular interest because this illici drug is widely abused chronically and most of the potential therapeutic uses may also require chronic administration. The presence or absence of ovarian hormones is of interest as a cofactor because: 1) ovarian hormones have direct and indirect influences on cognitive function, and 2) published data generated by these investigators indicate that the ovarian hormone estradiol can antagonize the detrimental effects of 9-THC on learning in female rats and alter the binding of cannabinoid ligands in brain areas that are critical for learning such as the hippocampus. For these same reasons, and because there is still a paucity of data regarding the effects of 9-THC on female animals, all of the planned behavioral experiments will use female rats and involve the presence or absence of ovarian hormones in 9- THC-treated subjects. In addition, the subjects in each treatment group will be sacrificed to examine potential changes in cannabinoid or estrogen receptors in relevant brain areas. Our overall hypothesis is that 17 �- estradiol can attenuate both the acute and chronic effects of 9-THC on memory in adult female rats and that a similar attenuation occurs in the hippocampus to affect its activity and role in memory. To address this hypothesis, experiments in Specific Aim 1 will determine whether ovarian hormones attenuate the acute disruptive effects of 9-THC on memory. In a similar manner, Specific Aim 2 will determine whether estradiol can attenuate the chronic effects of 9-THC on memory and facilitate the development of tolerance to those effects. Finally, Specific Aim 3 will determine whether estradiol can attenuate the disruptive effects of 9- THC on hippocampal activity. When completed, these data will demonstrate that estrogens in females can attenuate both the acute and chronic effects of �9-THC on memory, and that estrogen receptor (ER) signaling reduces cannabinoid receptor (CBR) signaling in brain areas critical for memory encoding.

PUBLIC HEALTH RELEVANCE: The current project proposes to investigate the interactive effects of the sex hormones with the acute and chronic effects of cannabinoids such as tetrahydrocannabinol ( 9-THC) in females. When this grant is completed, these experiments will provide a comprehensive picture of the interaction of estradiol and 9-THC, while also providing a mechanistic understanding of the manner in which they interact on hippocampal activity and the ramifications of this for females.