# Impact of Cannabinoid Across the Lifespan (ICAL)

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $402,830

## Abstract

ICAL BEHAVIORAL PROJECT: PROJECT SUMMARY
Early cannabis use is associated with long-term psychiatric risks including susceptibility to abuse of
harder drugs like opioids. Yet in humans it is difficult to determine the impact of adolescent THC exposure
(ado-THC) itself, versus underlying comorbidities or societal factors that also contribute to the
association. Despite their shortcomings, rodent models are thus still crucial for establishing causal,
biological influences of ado-THC on addiction susceptibility. Indeed, preclinical studies suggested that
ado-THC conveys later susceptibility to opioids. In the first funding period, we confirmed and
extended this finding, demonstrating that ado-THC causes a sex-dependent vulnerability in rats:
males show a pre-sensitized locomotor response to heroin, while females show greater heroin
place preference and economic demand for a fentanyl derivative. Regardless of founded criticisms
of the THC “gateway effect,” such robust findings, seen across labs and behavioral models, cannot be
ignored. How might adolescent THC promote opioid reward? Adolescence is a period of active brain
maturation, especially in late-developing structures like the prefrontal cortex (PFC). Microglia, the
resident immune cells of the brain parenchyma, play a key role in this process. Initially thought to respond
solely to insults by attaining an “activated” phenotype with cytokine release and other pro-inflammatory
processes, microglia do much more than counteract physical threats. Indeed, drugs of abuse like opioids
recruit incompletely understood microglial processes which seem to be essential for the acutely
reinforcing effects of opioids, as well as longer-term progression of use into addiction. Indeed, our
preliminary data support the hypothesis that ado-THC impact microglia in short and long
timeframes, and that these changes may be involved in the pro-opioid, sex-dependent phenotype.
We test this novel hypothesis in three Aims: 1) determining how ado-THC and heroin impact microglial
protein and RNA markers, and whether “resetting” microglia in adulthood selectively reverses ado-THC
behavioral effects, 2) determining the precise developmental stages at which ado-THC has the most
pronounced long-term pro-opioid effects, and 3) determining the mechanisms required for ado-THC to
have its persistent effects on microglia and behavior, and whether these are the same or different from
those underlying Molecular and Synaptic Project findings. These studies, especially in the context of our
integrated Center-wide research program, will break new ground in understanding the roles played by
microglia in opioid addiction, and in the neurodevelopmental consequences of adolescent use of drugs
like cannabis.

## Key facts

- **NIH application ID:** 10932782
- **Project number:** 2P50DA044118-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Stephen Vincent Mahler
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,830
- **Award type:** 2
- **Project period:** 2018-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932782

## Citation

> US National Institutes of Health, RePORTER application 10932782, Impact of Cannabinoid Across the Lifespan (ICAL) (2P50DA044118-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10932782. Licensed CC0.

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