Panayotis K Thanos, Ph.D. - US grants

Project summary: Addiction is a serious health and social problem in the United State and worldwide. Yet effective interventions to alleviate addiction-related disorders remain very limited. Recently, results from preclinical studies have established that endocannabinoids (eCBs) play a pivotal role in controlling reward- related behaviors and that dysregulated eCB signaling contributes to the development and persistence of addictive behaviors. Thus, elucidating the various mechanisms of eCB signaling in the brain reward circuit is required for a better understanding of the neurobiology of addiction-related disorders and the development of effective treatments. Over the past few years, studies from our laboratories have begun to unravel the mechanism of eCB transport at central synapses. The results of these studies have led to a novel hypothesis that fatty acid binding proteins control retrograde eCB signaling. In this application, we will use a multidisciplinary approach to test this hypothesis and delineate the precise role of FABPs in eCB signaling and function of the brain?s reward circuit and addiction-related behaviors. The ultimate objective of this application is to enhance our understanding of the eCB signaling and its role in controlling addiction-related behaviors, a necessary step toward the development of improved treatment strategies for addiction.

The broad goal of this application is to address the large public health problem of comorbid use of tobacco and cannabis during pregnancy and increase understanding of mechanisms of effect by using translational science with synergistic human and animal designs. This application consists of an R21 mechanism applied to an existing human sample recruited in the first trimester of pregnancy and assessed repeatedly from pregnancy to early school age, with new data to be collected in middle childhood; and an R33 mechanism applied to a new study using an animal model. The results of the human study have and will continue to inform the design of the animal model, and together, they will both inform the next steps in this program of research. The human study will have four groups of children, demographically matched controls, tobacco exposed, and light and heavy tobacco and cannabis exposed children, while the animal study will include light and heavy exposure groups for tobacco and cannabis and the combination of the two. The animal study will focus on the specific prenatal effects of nicotine (N) and Tetrahydrocannabinol (THC), as well as the combination N+THC during early adolescence and young adulthood. There are three specific aims: 1) to examine differences in body weight and behaviors that impact body weight across groups, with the goal of examining associations between prenatal exposure and obesity risk; 2) to examine differences in two critical aspects of cognitive function: attention and working memory; and 3) to examine mechanisms explaining risk including poor fetal growth (human), stress reactivity (human and animal), and inflammation (human and animal). These synergistic aims will then inform the larger program of research with the long term goal of understanding prenatal exposure effects on obesity and metabolic disorders, substance use and risk behaviors, and early aging among these high risk children. This translational study is of high impact in that it will help clinicians to make personalized treatment plans during pregnancy with important implications on childhood through adult health.