Early adolescent exposure to marijuana has been associated with increased addiction and mental illness, suggesting that marijuana use is a gateway to adverse outcomes. However, research on the effects of early marijuana exposure is hampered by the need for a robust rodent inhalation exposure paradigm and a clearly defined sensitive period of exposure. Program announcement # 14-162 recognizes these fundamental gaps in our knowledge, as well as the need for studies on the exposure to different potencies and constituencies of cannabis/cannabinoids in both sexes. Marijuana is composed of two main constituencies of interest: ?9-tetrahydrocannabinol (THC; the `high') or the cannabidiols (CBD; `medicinal marijuana'). The long-term goal is to identify key factors that are predictive of THC/CBD effects to develop improved strategies to reduce the unwanted, long-term effects of developmental marijuana exposure. The overall objective in this R21 application is to establish how different levels of inhaled marijuana constituents influence pharmacokinetics across age to identify a sensitive period when risky behaviors are effected by THC/CBD exposure in rats. Specifically, the central hypothesis is that higher levels of THC exposure will increase, and CBD exposure will reduce, respectively, risky behavior and addiction as a function of age of exposure and sex. The rationale for these studies is based on clinical observations that exposure to marijuana during early adolescence has been associated with increased addiction. Preliminary data show that exposure to inhaled 6% THC- containing NIDA marijuana cigarettes (0.02% CBD) produced age-dependent changes in THC blood levels and memory deficits, with the greatest impairment in early adolescence. Impairment on this same memory task predicts later cocaine self-administration. The central hypothesis will be tested by pursuing two specific aims: 1) determine the age- and sex- dependent effects on drug levels in rats following acute and chronic exposure to passive inhalation of different THC/CBD potencies in early adolescence, late adolescence and adulthood; and 2) determine early behavioral predictors of addiction risk following THC/CBD inhalation exposure. Whether a risky behavior is present before or after (or both) exposure to three different combinations of inhaled THC/CBD and then increases the amount of cocaine self- administration will be investigated. The approach is innovative, in the applicant's opinion, because the inhaled effects of CBD and/or THC on development have been neglected. The proposed research is significant because it is expected to address the classic ?chicken or the egg? question that is raised by the gateway hypothesis with the pre-/post- behavioral assessments. Successful development of an inhalation paradigm and the identification of a sensitive period will be used in future studies that examine the effects of marijuana exposure on brain development with anatomical and functional MRI.
Developmental Exposure to Inhaled Marijuana The proposed research is relevant to public health because knowing how inhaled marijuana, including both delta-9-tetrahydrocannabidol (THC, used recreationally) and cannabinoids (CBDs, used medicinally) effect brain development is important as the potency of THC has risen by more than 8-fold than what it was 20 years ago. The current study is one of the first to focus on how different amounts of inhaled THC, CBD, or both THC and CBDs, influence risk for addiction at different stages of development in males and females. This investigation is expected to increase reproducibility to the human population by accounting for how marijuana is administered and the increased concentrations that are now available to teens.