Notice of Special Interest: Exploring the Effects of Endocannabinoids and Exogenous Cannabinoids on Brain Development

Notice Number: NOT-DA-25-030

Expiration Date: May 8, 2028

Purpose

The purpose of this Notice of Special Interest (NOSI) is to encourage investigators to submit grant applications to the National Institute on Drug Abuse (NIDA) to investigate the roles of endocannabinoids and the effects of cannabinoid exposure in the developing brain, from fetal development through young adulthood in humans and animal models.

Funding mechanisms: R01, R21, R03, K01, K08, K25, K99, F32

Background

The dramatic increase in cannabis and cannabinoid use among pregnant people and young adults has the potential to result in adverse psychiatric, cognitive, and behavioral disorders throughout the lifespan. The endogenous cannabinoid system plays a critical role in brain development during embryogenesis and adolescence. The endocannabinoid system affects neurogenesis, neuronal and glial differentiation, axonal elongation, and pathfinding, as well as synaptic growth and neural circuit modulation. For example, the formation of the projections from the striatum to the substantia-nigra requires the activation of CB1 receptors. CB1 receptors have also been shown to be required for the development of the thalamocortical projections and the columnar organization of cortical columns in the cortex.

Exogenous exposure to cannabinoids such as THC, one of the active ingredients in the cannabis plant, leads to suppression of GABA inputs and the disruption of synaptic integration during development in the prefrontal cortex, hippocampus, and cerebellum. Exogenous cannabinoid exposure has also been shown to be associated with the impairments of the developing glutamatergic, GABAergic, dopaminergic, opioidergic and serotonergic systems, especially in the cerebral cortex, basal ganglia, hippocampus, ventral tegmental area, and cerebellum. These observations in animals may explain the findings that cannabis use during pregnancy increase the risk of psychosis, substance use, and other behavioral problems in offspring. The mechanisms by which exogenous cannabinoid exposure affects brain development remain understudied.

Gaps in knowledge that can be addressed by research supported by this NOSI include:

  • What is the role that endocannabinoids and cannabinoids play in the development of the mesolimbic dopamine systems and in systems that modulate reward?
  • What are the mechanisms and critical periods by which endocannabinoids and exogenous cannabinoids influence pattern formation, neural proliferation, neuronal migration and differentiation, axonal pathfinding, synapse formation and synaptic plasticity, and synapse elimination?
  • How does exposure to exogenous cannabinoids in utero or during adolescence affect neural substrates or circuits that govern behavior and cognition?
  • How do genetic, epigenetic, and environmental factors modify the effect of exogenous cannabinoids on development?
  • What mechanisms regulate the temporal and spatial expression of cannabinoid receptors and ligands?

For more information, please see the opportunity webpage.