Mechanisms for predisposition to AUD following prenatal alcohol and THC comorbidity - PROJECT SUMMARY
The high rate of prenatal alcohol use combined with an increase in marijuana prevalence and acceptance in
society today, has led to an increase in comorbid maternal alcohol and cannabinoid exposure with little
understanding of the potential lasting effects on offspring. Prenatal cannabinoid and alcohol exposure are known
to alter neurodevelopment and induce lasting behavioral changes including higher rates of alcohol and drug
abuse later in life. Δ9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, binds
cannabinoid receptors and activates the endocannabinoid (EC) system. The EC system is critically involved in
brain development and modulates synaptic transmission processes, including those in the central nucleus of the
amygdala (CeA; a hub of stress/anxiety processing critical to the development of addiction). Disruption of the
EC system through prenatal drug use is thought to underlie a predisposition for those individuals to addictive
behaviors. Using a model of prenatal THC, alcohol, or both vapor exposure (PTE, PAE, and PTAE, respectively),
my K99/R00 Pathway to Independence proposal aims to identify if PTE and/or PAE perturb or impact
development to cause long lasting alterations in 1) anxiety-like behaviors, 2) motivation to seek and consume
alcohol, 3) CeA neurotransmission, and 4) underlying CeA EC signaling in a sex-specific manner. My preliminary
results indicate lasting, sex-specific changes in anxiety-related behaviors, as well as changes in EC signaling in
the CeA, a region unexplored with PTE and comorbid PAE.
My goal is to develop an independent research project utilizing a multitude of techniques to approach the
issue of maternal alcohol and cannabinoid use at all levels. This holistic approach includes combining behavior,
electrophysiology, targeted pharmacology, molecular, optical, and omics techniques to elaborate on the
developmental outcomes induced by THC and alcohol parental insult. During the K99 phase I will identify the
consequences of PAE and/or PTE (via vapor inhalation) on the predisposition of offspring to consume alcohol
and anxiety-like behaviors later in life (under the mentorship of Drs. Thomas and Roberts); on the lasting
mechanistic alterations in CeA neuronal functions and EC signaling (under the mentorship of Dr. Roberto); and
on in vivo activity of a key EC regulating enzyme Fatty Acid Amide Hydrolase (FAAH) using novel optical tools
with bioluminescence imaging technology (under the mentorship of Dr. Roberts). The training I will receive during
this award will equip me with the multidisciplinary techniques needed to continue this research independently to
investigate the mechanisms underlying these PTE and PAE-induced alterations in the CeA during the R00 phase
(with guidance from my advisory team: Drs. Lovinger, Valenzuela, Cravatt, Christie, Mayfield, and Miller).
Overall, this project will provide mechanistic insight into the effects of PTE, PAE and comorbid PTAE on later in
life addictive behaviors and physiological function in the CeA that may implicate candidate pathways for further
investigation and/or treatment strategies.
