Impact of Cannabinoid Across the Lifespan (ICAL)

ICAL MOLECULAR 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, electrophysiological, morphological, and behavioral approaches to test the hypothesis that adolescent cannabis use reprograms the endocannabinoid (ECB) 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, the Molecular Project showed that daily adolescent (not adult) exposure to Δ9-tetrahydrocannabinol (THC) produces in male and female mice a lasting disruption of microglial homeostasis, which is prevented by co- administration of a CB1 (not CB2) cannabinoid receptor antagonist and is characterized by suppressed transcription of genes involved in host defense and by deficits in the responses to psychosocial stress and microbial infection. Furthermore, the Project found that the ECB-degrading enzyme, FAAH, is required for the establishment of this state. Importantly, experiments by the Synaptic and Behavioral Projects showed that mice and rats treated with THC in adolescence exhibit profound and highly specific impairments in synaptic plasticity, memory, and the rewarding properties of opioids, most (albeit not all) of which may also be rooted in microglial malfunction. Working in close collaboration with other ICAL teams, the Molecular Project will test two specific hypotheses: (i) the establishment of THC-induced microglial dysfunction is a cell-autonomous process driven by FAAH expression in microglia; and (ii) once established, microglial dysfunction produces long- term changes in neuronal gene transcription. We have three aims: (1) Characterize THC-induced FAAH expression in microglia; (2) Determine whether THC-induced FAAH expression mediates microglial dysfunction; (3) Examine the impact of THC-induced microglial dysfunction on neuronal transcription. A mechanistic understanding of the lasting consequences of THC exposure will (i) guide the research activities of other ICAL Projects; (ii) provide a mechanistic framework in which to interpret epidemiological datasets on the health impact of adolescent substance use; and (iii) accelerate the discovery of medications aimed at correcting the neurobehavioral consequences of teenage cannabis use.