# Sex-specific critical periods determine the effects of cannabinoids on the mesocorticolimbic system

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2020 · $309,985

## Abstract

Cannabis is the most frequently used illicit drug. Its widespread use in adolescents is associated with an
increased risk for mental illness and is a major public health concern. For example, an increased rate of
psychosis and an earlier onset of psychotic illness have been observed with heavy adolescent cannabis use.
There is also a correlation between early cannabis use, the age at onset of psychotic disorders and the age at
first hospitalization for 'pure' cannabis users. However, the pathophysiological mechanisms underlying the
adverse effects of early cannabis use, such as perturbed social interactions, psychosis and addiction risk
remain to be elucidated. A better understanding of these mechanisms is necessary to develop therapies &
effective prevention programs, and to inform decisions on public policy, including cannabis legalization.
Adolescence is a period of profound neurodevelopmental maturation, notably in the mesocortico-limbic system
(MCS), an ensemble of interconnected structures involved in higher cognitive functions, emotions, reward and
social behaviors. MCS development occurs at different rates in males and females. During adolescence, social
play, an MCS-based behavior, guides the emergence and proper maturation of social interactions. Disruption
of social play in the adolescent negatively affects adult behaviors. Impaired adolescent social play may also be
a sign of emerging psychopathology. The main psychoactive ingredient of cannabis (i.e., THC) engages the
abundant CB1 cannabinoid receptor (CB1R), competing with endogenous cannabinoids. CB1Rs are a core
component of the endogenous cannabinoid system (ECS). The ECS is abundant throughout the MCS and
modulates many neurodevelopmental, neuronal and synaptic processes, including adolescent social play.
Recent discoveries from our laboratories fueled the concept that ECS dysfunction plays a key role in diverse
neuropsychiatric diseases of environmental or genetic origin.
Motivated by new, unpublished data, and using a rodent model, we propose a multi-disciplinary approach to
establish the sex-specific development and distribution of ECS components in the MCS and how these affect
the molecular, synaptic and behavioral consequences of adolescent cannabis (THC) exposure. Our 3 aims will:
1/ Characterize and compare the normal functional development of neuronal and synaptic responses in
the MCS between male and female rats from pre-adolescence to adulthood.
2/ Establish the developmental patterns of expression and localization of key components of the ECS
in the rat MCS in a sex and age-specific fashion.
3/ Determine the sex-specific functional (molecular, synaptic, and behavioral) consequences of THC
exposure during critical periods of adolescence and adulthood.
Together, the results of these studies will define new structural, molecular and functional synaptic substrates of
the sex-specific effects of adolescent cannabis use on ECS function and behavior.

## Key facts

- **NIH application ID:** 9936374
- **Project number:** 5R01DA043982-04
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** OLIVIER JJ MANZONI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,985
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936374

## Citation

> US National Institutes of Health, RePORTER application 9936374, Sex-specific critical periods determine the effects of cannabinoids on the mesocorticolimbic system (5R01DA043982-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936374. Licensed CC0.

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