The cannabinoid receptor 1 gene (CNR1) has emerged as a promising contributor to CD vulnerability. CNR1 is located in 6q14–15 and encodes a seven transmembrane signaling protein, i.e., the cannabinoid receptor 1 (CB1), which is preferentially distributed in the presynaptic membrane of neurons (Di Marzo et al 2004). Delta-9-tetrahydrocannabinol (THC), the main active ingredient in marijuana, is an exogenous ligand for CB1. Anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG) are the two major known endogenous ligands for CB1. Both AEA and 2-AG act as retrograde messengers, moving backward across the synapse from the postsynaptic neuron, and binding to CB1 to depress neurotransmitter release either transiently or over a longer time course (Chevaleyre et al 2006; Lupica and Riegel 2005). Neurobiological studies show that CB1 is one of the most abundant neuromodulators in the mammalian brain, including neocortex, hippocampus, basal ganglia, cerebellum, striatum, and the ventral tegmental area (VTA) (Arnold 2005; Di Marzo et al 2004; Herkenham et al 1990; Mailleux and Vanderhaeghen 1992; Solinas et al 2008; Tsou et al 1998).
