# Impact of Cannabinoid Across the Lifespan (ICAL)

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $592,501

## Abstract

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.

## Key facts

- **NIH application ID:** 10932780
- **Project number:** 2P50DA044118-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Daniele Piomelli
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $592,501
- **Award type:** 2
- **Project period:** 2018-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932780

## Citation

> US National Institutes of Health, RePORTER application 10932780, Impact of Cannabinoid Across the Lifespan (ICAL) (2P50DA044118-05A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10932780. Licensed CC0.

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