The Effects of Prenatal Alcohol and Cannabis on Vulnerability to Later Drug Use Disorders - PROJECT SUMMARY Prenatal alcohol exposure disrupts physical, brain, and behavioral development, leading to a range of fetal alcohol spectrum disorders (FASD), a serious, global, and costly public health concern. But alcohol is often not the only drug consumed during pregnancy and there is rising concern of the potential consequences of prenatal cannabis exposure, as cannabis products have increased in accessibility and acceptance. Unfortunately, many pregnant women believe that cannabis use during pregnancy does not pose a threat to the fetus, even though the consequences of prenatal cannabis, alone or in combination with alcohol, are poorly understood. Interestingly, prenatal cannabis and alcohol exposure can alter neurodevelopment and induce lasting behavioral changes, and both are associated with higher rates of alcohol and drug abuse later in life. Δ9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, binds to cannabinoid receptors and activates the endocannabinoid (eCB) system. Similarly, alcohol may impact the eCB system, creating a common target for both prenatal THC and alcohol. The eCB system is critically involved in brain development and modulates synaptic transmission processes in the central nucleus of the amygdala (CeA), a brain region involved in motivation for drug use and anxiety-related disorders. Disruption of the eCBs through prenatal drug exposure is thought to underlie a predisposition to addictive behaviors. Using a rodent model of prenatal alcohol, THC, or the combination via vapor exposure, this proposal aims to identify if prenatal exposure impacts development to cause long-lasting alterations in 1) anxiety-like behaviors, 2) motivation to seek and consume alcohol later in life, 3) CeA neurotransmission, and 4) CeA eCB signaling in an age- and sex-specific manner. Our preliminary data indicate lasting, sex-specific changes in anxiety-related and risk-taking behaviors, as well as changes in components of eCB signaling in the CeA, a region unexplored with prenatal THC and alcohol exposure. Our proposal will use a multidisciplinary approach to investigate the consequences of prenatal alcohol and cannabis exposure, by combining behavioral, molecular, and electrophysiological techniques. We will identify the consequences of prenatal alcohol and/or THC (via vapor inhalation) on the predisposition of offspring to consume alcohol and anxiety-like behaviors later in life and the lasting mechanistic alterations in CeA neuronal functions and eCB signaling. Overall, this project will provide mechanistic insight into the effects of prenatal THC, alcohol, and combined exposure on addictive behaviors and physiological function in the CeA that may implicate candidate pathways, such as the endocannabinoid system, for further investigation and/or treatment strategies.
