The involvement of the CB1R in the above-described effects of cannabinoids was usually verified by blockade of the receptor, using an antagonist/inverse agonist, such as the most known rimonabant [86] or AM251 [86]. However, opposing results have also been shown by some studies in which it was reported that the antagonist SR141716A (structurally comparable to rimonabant) and AM251 exerted antidepressant-like effects in animal models [87,88,89,90]. In the case of rimonabant, the effects were similar to those of antidepressant fluoxetine in various animal models of depression [90]. Moreover, such an effect was absent from the gene-deleted CB1−/− mouse treated with AM251, indicating a role for the CB1 receptor in depression. The mechanism underlying the antidepressant-like effects of rimonabant and other antagonists or inverse agonists remains to be determined, especially since rimonabant in humans has shown pro-depressive, pro-anxiogenic and even ideations of suicide, as will be described later. In contrast, multiple animal studies have shown that the blockade of CB1R signaling in rodents results in anhedonia-like behavior [91], and heightened levels of basal anxiety [92,93,94], and in general, an increased tendency to
