Kivonat:
CB 1 receptor antagonists were among the most
promising drug targets in the last decade. They have been
explored and found to be effective as therapeutic agents for
obesity and related cardiometabolic problems; however, use of
rimonabant, the first marketed CB 1 receptor
antagonist, has been suspended because of its anxiogenic and
depressogenic side effects. Because some other antiobesity
drugs, like dexfenfluramine or sibutramine, were also suspended,
the unmet need for drugs that reduce body weight became
enormous. One approach that emerged was the use of CB
1 receptor antagonists that poorly cross the blood brain
barrier, the second, the development of neutral antagonists
instead of inverse agonists, and the third, use of personalized
medicine, namely the selection of the patient population without
psychiatric side effects. In this review, we dissect the
peripheral and central mechanisms involved in the effects of CB
1 receptor antagonists and argue that central mechanisms are
more or less involved in most cardiometabolic therapeutic
effects and thus, among patients with unsatisfactory therapeutic
response to compounds with peripheral action, centrally acting
antagonists may be needed. An analysis of pharmacogenetic
factors may help to identify persons who are at no or low risk
for psychiatric adverse effects. Here, we present the models and
identify molecular mechanisms and receptors involved in the
effects of stress-, anxiety- and depression-related
neurocircuitries sensitive to CB 1 receptor
antagonists, like the serotonergic, noradrenergic and
dopaminergic systems, which are not only regulated by CB
1 receptors, but also regulate the synthesis of the
endocannabinoid 2-arachidonoyl-glycerol. © 2011 Scandinavian
Physiological Society.