The goal of this study was to help develop inhibitors for Fatty Acid Binding Proteins (FABPs) in the brain to aid in new treatments of anxiety disorders and addiction.
The endocannabinoid (eCB) system composed of the CB1 and CB2 receptors, their endogenous lipid agonists known as endocannabinoids (i.e. anandamide and 2-arachidonoylglycerol) and the enzymes that produce and metabolize the endocannabinoids has emerged as a key regulator of stress homeostasis and addiction. It is generally accepted that a dysfunction of the eCB system is a major contributor factor to stress-related mental disorders including anxiety, depression and additions. Indeed, results from behavioral studies in animal have reported that blockade of CB1 receptors or inhibition of eCBs synthesis, manipulation that reduces eCB signaling increases anxiety and alter addiction-related behaviors. In contrast, enhancement of eCB signaling via blockade of eCB hydrolysis and/ or uptake exerts anxiolytic–like effects and reduces the behavioral responses to drugs of abuse. Collectively, these preclinical studies suggest that drugs that modulate eCB signaling, including anandamide, represent new strategy for the treatment of anxiety disorders and addiction. However, progress along this line of research requires a better understanding of the various mechanisms that regulate eCB signaling, in particular the role of Fatty Acid Binding Proteins (FABPs), key intracellular anandamide transporters in the regulation of eCB function. In this application, we seek to address these issues by directly assessing the impact of selective inhibition or genetic deletion of FABPs on eCB-mediated modulation of glutamate synapses of ventral tegmental area dopamine neurons, a brain area critically involved in the regulation of stress homeostasis and addictions.
Samir Haj-Dahmane, PhD
Research Institute on Addictions
Martin Kaczocha, PhD
Stony Brook University