Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice

Delta(9)-Tetrahyhrocannabinol (Delta(9)-THC), the major psychoactive ingred ient in preparations of Cannabis sativa (marijuana, hashish), elicits centr al nervous system (CNS) responses, including cognitive alterations and euph oria. These responses account for the abuse potential of cannabis, while ot her effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB I cannabinoid receptor, we have produced a mouse strain with a disrupted CB 1 gene. CB1 knockout mice appeared healthy and fertile, but they had a sign ificantly increased mortality rate. They also displayed reduced locomotor a ctivity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta(9)-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CBI mutant mice. In contrast, rye still found Del ta(9)-THC-induced analgesia in the tail-flick test and other behavioral (li cking of the abdomen) and physiological (diarrhea) responses after Delta(9) -THC administration. Thus, most, but not all, CNS effects of Delta(9)-THC a re mediated by the CB1 receptor.