Analysis of the endocannabinoid system by using CB1 cannabinoid receptor knockout mice

The endocannabinoid system has been involved in the control of several neurophysiological and behavioural responses. To date, three lines of CB1 knockout mice have been established independently in different laboratories. This chapter reviews the main results obtained with these lines of CB1 knockout mice in several physiological responses that have been previously related to the activity of the endocannabinoid system. Studies using CB1 knockout mice have demonstrated that this receptor participates in the control of several behavioural responses including locomotion, anxiety- and depressive-like states, cognitive functions such as memory and learning processes, cardiovascular responses and feeding. Furthermore, the CB1 cannabinoid receptor is involved in the control of pain by acting at peripheral, spinal and supraspinal levels. The involvement of the CB1 cannabinoid receptor in the behavioural and biochemical processes underlying drug addiction has also been investigated. These CB1 knockouts have provided new findings to clarify the interactions between cannabinoids and the other drugs of abuse such as opioids, psychostimulants, nicotine and ethanol. Recent studies have demonstrated that endocannabinoids can function as retrograde messengers, modulating the release of different neurotransmitters, including opioids, gamma-aminobutyric acid (GABA), and cholecystokinin (CCK), which could explain some of the responses observed after the stimulation of the CB1 cannabinoid receptor. This review provides an update of the apparently controversial data reported in the literature using the three different lines of CB1 knockout mice, which seem to be mainly due to the use of different experimental procedures rather than any constitutive alteration in these lines of knockouts.