The endogenous cannabinoid system is an ubiquitous lipid signalling system that appeared early in evolution and which has important regulatory functions throughout the body in all vertebrates. The main endocannabinoids (endogenous cannabis-like substances) are small molecules derived from arachidonic acid, anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol. They bind to a family of G-protein-coupled receptors, of which the cannabinoid CB(1) receptor is densely distributed in areas of the brain related to motor control, cognition, emotional responses, motivated behaviour and homeostasis. Outside the brain, the endocannabinoid system is one of the crucial modulators of the autonomic nervous system, the immune system and microcirculation. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and serve as retrograde signalling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters, including dopamine. Endocannabinoids are transported into cells by a specific uptake system and degraded by two well-characterized enzymes, the fatty acid amide hydrolase and the monoacylglycerol lipase. Recent pharmacological advances have led to the synthesis of cannabinoid receptor agonists and antagonists, anandamide uptake blockers and potent, selective inhibitors of endocannabinoid degradation. These new tools have enabled the study of the physiological roles played by the endocannabinoids and have opened up new strategies in the treatment of pain, obesity, neurological diseases including multiple sclerosis, emotional disturbances such as anxiety and other psychiatric disorders including drug addiction. Recent advances have specifically linked the endogenous cannabinoid system to alcoholism, and cannabinoid receptor antagonism now emerges as a promising therapeutic alternative for alcohol dependence and relapse.

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Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.

Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoidrelated genes in key brain regions of reward and dependence, and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines. A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats, and was accompanied by decreased enzyme activity in this region. Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand 3 [H]SR141716A, and [35S]GTPgS incorporation stimulated by the CB1 agonist WIN 55,212-2 were downregulated in the same area. Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals, and a compensatory downregulation of CB1 signaling. The functional role of impaired FAAH function for alcohol self-administration was validated in two independent ways. The CB1 antagonist SR141716A potently and dose-dependently suppressed self-administration in AA rats when given systemically, or locally into the PFC, but not in the striatum. Conversely, intra-PFC injections of the competitive FAAH inhibitor URB597 increased ethanol self-administration in nonselected Wistar rats. These results show for the first time that impaired FAAH function may confer a phenotype of high voluntary alcohol intake, and point to a FAAH both as a potential susceptibility factor and a therapeutic target.

We report a detailed analysis of the distribution of relevant proteins of the endogenous cannabinoid system in the rat cerebellum (cerebellar cortex and deep cerebellar nuclei) and the two functionally related nuclei, the vestibular nuclei and the inferior olive. These proteins include the two main cannabinoid receptors (CB(1) and CB(2)), the enzymes involved in cannabinoid biosynthesis (DAGL alpha, DAGL beta, and NAPE-PLD), and the endocannabinoid-degradating enzymes (FAAH and MAGL). With regard to the cerebellar cortex, these data confirm several published reports on the distribution of cannabinoid CB(1) receptors, DAGL alpha, MAGL, and FAAH, which suggests a role of endocannabinoids as retrograde messengers in the synapses of the Purkinje cells by either parallel fibers of granule cells or climbing fibers from the inferior olive or GABAergic interneuron. Additionally, we describe the presence of CB(2) receptors in fibers related to Purkinje somata (Pinceau formations) and dendrites (parallel fibers), suggesting a potential role of this receptor in the retrograde cannabinoid signaling. A remarkable finding of the present study is the description of the different elements of the endogenous cannabinoid system in both the main afferent nuclei to the cerebellar cortex (the inferior olive) and the efferent cerebellar pathway (the deep cerebellar nuclei). The presence of the endogenous cannabinoid system at this level establishes the basis for endocannabinoid-mediated synaptic plasticity as a control mechanism in motor learning, opening new research lines for the study of the contribution of this system in gait disorders affecting the cerebellum.