Mice that can’t get high

Abstract

Humans have been experimenting with extracts of the plant Cannabis sativa for thousands of years, for medicinal and recreational purposes, and usually in blissful ignorance of the underlying pharmacology. In recent history, it has been shown that there are two mammalian receptors for cannabinoids that presumably respond normally to the endogenous ligand, anandamide. The CB1 receptor is expressed primarily in the brain, whereas the CB2 receptor is found in the immune system. The creation of CB1 knockout mice1,2 has both clarified and complicated our understanding of the effects of cannabinoids. As expected, these mice lack all specific binding of cannabinoid agonists in the central nervous system and lose most, but not all, of the physiological responses to cannabinoids. Behaviourally, the knockout mice are less pain-sensitive in supraspinal pain responses and have reduced locomotor activity. They are extremely hypoactive in a test for exploratory activity, although no different from normal mice when challenged with balancing on a rotating beam. Paradoxically, the behavioural changes resemble the direct effects of cannabinoids, perhaps as a result of adaptive neuronal changes in the mutant mice. Significant alterations in neuropeptide levels were indeed found in some parts of the brain that normally express high CB1 levels. Some of the other phenotypes are also puzzling. The CB1 knockout mice exhibit a sixfold increase in mortality rate, dying suddenly for no obvious reason. When treated with a high dose of Δ9-THC, the major psychoactive ingredient in marijuana, the knockout mice fail to show normal effects such as catalepsy, hypomobility and hypothermia, but instead assume a hunched posture, frequently lick their abdomens and suffer from strong diarrhoea. These responses are not seen in wild-type mice, but are also present in CB1–CB2 double knockout mice, so there must be effects of cannabinoids that are not mediated through the known receptor pathways.