Genetic Dissection of Behavioural and Autonomic Effects of Δ9-Tetrahydrocannabinol in Mice

Abstract

Marijuana and its main psychotropic ingredient Δ⁹-tetrahydrocannabinol (THC) exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1), which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release γ aminobutyric acid), cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in all principal neurons abolished or strongly reduced the behavioural and autonomic responses to the drug. Moreover, locomotor and hypothermic effects of THC depend on cortical glutamatergic neurons, whereas the deletion of CB1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of the drug. These data show that several important pharmacological actions of THC do not depend on functional expression of CB1 on GABAergic interneurons, but on other neuronal populations, and pave the way to a refined interpretation of the pharmacological effects of cannabinoids on neuronal functions. Marijuana and its main psychoactive component, THC, exert a plethora of behavioural and autonomic effects on humans and animals. Some of these effects are the cause of the widespread illicit use of marijuana, while others might be involved in the potential therapeutic use of this drug for the treatment of several neuronal disorders. The great majority of these effects of THC are mediated by cannabinoid receptor type 1 (CB1), which is abundantly expressed in the central nervous system. The exact anatomical and neuronal substrates of each action are, however, not clearly known at the moment. We addressed this issue by using an advanced genetic approach. Control and conditional mutant mice, lacking CB1 expression in defined neuronal subpopulations but not in others, were treated with THC, and typical effects of the drug on motor behaviour, pain, and thermal sensation were scored. Our results show that different neuronal subpopulations mediate different effects of THC and could lead to a refined interpretation of the pharmacological actions of cannabinoids. Moreover, these data might provide the rationale for the development of drugs capable of selectively activating CB1 in specific neuronal subpopulations, thereby better exploiting cannabinoids' potential therapeutic properties.