ICAL ANIMAL CORE: PROJECT SUMMARY The Center of Excellence Impact of Cannabinoids Across the Lifespan (ICAL), the renewal of which is proposed in this revised application, deploys a vertically integrated strategy that combines molecular, synaptic, and behavioral approaches to test the hypothesis that adolescent cannabis use reprograms the endocannabinoid signaling system at the molecular and cellular level, producing persistent abnormalities in its function and, ultimately, in cognition and motivated behavior. In the first funding period, which lasted 4 years, the Animal Core (1) developed and validated (in collaboration with the Analytical Core) a THC treatment regimen that captures key features of daily cannabis use in adolescence, a use pattern that is increasingly common among teenagers [80]; (2) produced ~5,000 animal subjects for ICAL projects and pilot grantees; (3) created a public repository of tissues from male and female mice and rats treated with THC in adolescence, which distributed >500 biospecimens to six laboratories in the USA and abroad in a period of ~12 months; (4) characterized the adult metabolic, nociceptive, and immune phenotype of mice of both sexes exposed to THC in adolescence. The studies have produced three published articles and one in preparation. In this renewal, the Core has three aims: Aim 1: Continue to implement ICAL’s THC treatment protocol to support projects and seed grantees. The Core will also conduct focused phenotyping investigations on the impact of THC on processes that (a) can affect the interpretation of data generated by ICAL projects; and/or (b) may have direct or indirect repercussions on cognition, affect, and motivation. Aim 2: Maintain and expand ICAL’s tissue repository. The Core will increase the bank’s inventory and aggressively publicize its services through periodic email and social media campaigns. Aim 3: Produce genetically modified mouse lines for ICAL projects. The experiments proposed in this renewal application require the development of several mouse lines carrying cell- selective deletions of CB1 cannabinoid receptor or fatty acid amide hydrolase. The Core will (a) generate the lines from available ‘flanked by LoxP’ (‘floxed’) and Cre recombinase mutants; (b) characterize their pharmacokinetic profile after THC administration; and (c) make them available for ICAL projects and the research community.