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

TLDR

THC elicits CNS effects such as euphoria and cognitive changes that drive its abuse potential, while its analgesic properties suggest therapeutic uses. The study aimed to investigate the role of the CB1 cannabinoid receptor by generating a CB1‑knockout mouse strain. The authors created a mouse line with a disrupted CB1 gene to serve as a model for CB1 function. CB1 knockout mice showed increased mortality, reduced locomotion, heightened catalepsy, and hypoalgesia in hotplate and formalin tests, lacked THC‑induced catalepsy, hypomobility, and hypothermia, yet retained THC‑induced analgesia in the tail‑flick test, indicating that most but not all THC CNS effects are mediated by CB1.

Abstract

Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor.