Chapter 5 THE ENDOCANNABINOID SYSTEM AS A TARGET FOR NOVEL ANXIOLYTIC AND ANTIDEPRESSANT DRUGS

Observational studies in humans suggest that exposure to marijuana and other cannabis-derived drugs produces a wide range of subjective effects on mood tone and emotionality. These observations have their counterpart in animal studies, showing that cannabinoid agonists strongly affect emotional reactivity in directions that vary depending on dose and context. Based on these evidence, the activation of central CB(1) receptor has emerged as potential target for the development of antianxiety and antidepressant therapies. However, the variable effects of exogenous cannabinoid agonists have gradually shifted the interest to the alternative approach of amplifying the effects of endogenous cannabinoids (EC), namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), by preventing their deactivation. The enzyme fatty acid amide hydrolase (FAAH) has been the target of intense research efforts aimed at developing potent and selective inhibitors that might prolong AEA actions in vivo. Among the inhibitors developed, the compound URB597 was found to potently inhibit FAAH activity in vivo and cause brain AEA levels to increase. Interestingly, the enhanced AEA tone produced by URB597 does not result in the behavioral effects typical of a direct-acting cannabinoid agonist. Though URB597 does not elicit a full-fledged cannabinoid profile of behavioral responses, it does elicit marked anxiolytic-like and antidepressant-like effects in rats and mice. Such effects involve the downstream activation of CB(1) receptors, since they are attenuated by the CB(1) antagonist SR141716 (rimonabant). Parallel to FAAH inhibition, similar results can also be observed by pharmacologically blocking the AEA transport system, which is responsible of the intracellular uptake of AEA from the synaptic cleft. The reason why FAAH inhibition approach produces a smaller set of cannabimimetic effects might depend on the mechanism of EC synthesis and release upon neuronal activation and on the target selectivity of the drug. The mechanism of EC release is commonly referred to as "on request", since they are not synthesized and stored in synaptic vesicles, such as classical neurotransmitters, but are synthesized from membrane precursors and immediately released in the synaptic cleft following neuronal activation. The neural stimulation in specific brain areas, for example, those involved in the regulation of mood tone and/or emotional reactivity, would result in an increased EC tone in these same areas, but not necessarily in others. Therefore, inhibition of AEA metabolism activity could amplify CB(1) activation mainly where AEA release is higher. Furthermore, the inhibition of FAAH causes an accumulation of AEA but not 2-AG, which, being 200-fold more abundant than AEA in the brain, might differently modulate CB(1)-mediated behavioral responses. The evidence outlined above supports the hypothesis that the EC system plays an important role in anxiety and mood disorders and suggests that modulation of FAAH activity might be a pharmacological target for novel anxiolytic and antidepressant therapies.