Two well-characterized cannabinoid receptors associated with the endocannabinoid signaling system, CB1 (CNR1) and CB2 (CNR2), have been reported to be associated with vulnerability to psychiatric disorders, including substance abuse (130). Studies using CNR1-knockout mice have reported that the mice display alterations in reward- and drug-seeking behaviors in response to psychostimulants, including alcohol (25, 106), nicotine (32, 44), cocaine, and amphetamine (90). The most-studied genetic variant in CNR1 is the (AAT)n tri-nucleotide short-tandem repeat, which was reported to be associated with intravenous administration of drugs of abuse (26). However, other studies have not confirmed this finding (10, 29, 85). Several other variants in CNR1 have been reported to be associated with cannabis dependence (3), cannabis-dependence symptoms (66), cocaine dependence (151), and other substance dependences (63, 115, 150).
