# Aberrant prefrontal cortical plasticity and neurobehavioral consequences of adolescent marijuana

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $402,563

## Abstract

The escalation in recreational use of marijuana by today’s teenagers is a major health concern, because of the
increased risk for psychiatric disorders in individuals who abuse marijuana during adolescence. The
psychiatric symptoms include abnormalities in cognitive functions that are mediated largely through the
prefrontal cortex (PFC) and associated limbic brain regions. Both pyramidal cells and interneurons in the PFC
express cannabinoid-1 receptors (CB1Rs) that are activated by endocannabinoids and by Δ9-tetrahydro-
cannabinol (Δ9-THC), the major psychoactive compound in marijuana. Chronic activation of these receptors by
Δ9-THC downregulates the endocannabinoid system that is a key regulator of experience-dependent learning
in the still immature PFC of adolescence. This learning is triggered by calcium influx through glutamatergic
NMDA receptors comprised of subunits that are physically and functionally coupled to dopamine D1-like
receptors (D1Rs). Pyramidal cells expressing D1Rs are among the PFC neurons most implicated in controlling
subcortical brain networks that drive cognitive, social, and attentional functions that are often dysfunctional in
psychiatric patients. These neurons are activated not only through Gs-coupled D1Rs and NMDA receptors,
but also through Gq/ii-coupled M1 muscarinic acetylcholine receptors (M1Rs) that provoke calcium release
from IP3-operated intracellular stores and also mediate endocannabinoid-dependent inhibition. However,
there is a major gap in knowledge of the extent to which adolescent abuse of marijuana produces changes in
the availability and functionality of these receptors in PFC neurons, which culminate in cognitive or social
dysfunctions in adulthood. The proposed studies will test the Central Hypothesis that adult behavioral
dysfunctions resulting from chronic adolescent administration of Δ9-THC are maintained by persistent
suppression of NMDA/D1R and M1R/IP3 receptor systems that mediate the influx and intracellular release of
calcium in dopamine-regulated prefrontal cortical neurons. The research will be conducted in male and female
C57BL/6J mice that are available in wild-type and mutant forms that can be used for determining potentially
critical sex-specific differences in the deleterious effects of adolescent marijuana, which are not directly
assessable in humans. The first two Specific Aims will assess the potentially deleterious impact of chronic
adolescent administration of Δ9-THC on the functional expression of ionotropic (NMDA) glutamate receptors
and muscarinic (M1) acetylcholine receptors in D1R-containing output neurons within the adult PFC. Specific
Aim 3 will assess the functional relevance of observed THC-induced changes in these receptor systems by
examining whether they are accompanied by (1) depression of intracellular Ca2+ and (2) behavioral
dysfunctions recapitulated by genetic or pharmacological disruption of NMDA/D1 or M1R/IP3 signaling in the
prefrontal cortex. Together, this ...

## Key facts

- **NIH application ID:** 9981716
- **Project number:** 5R01DA042943-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** VIRGINIA M PICKEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,563
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981716

## Citation

> US National Institutes of Health, RePORTER application 9981716, Aberrant prefrontal cortical plasticity and neurobehavioral consequences of adolescent marijuana (5R01DA042943-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981716. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*