Endocannabinoid-serotonin systems interaction in health and disease

Endocannabinoid (eCB) and serotonin (5-HT) neuromodulatory systems work both independently and together to finely orchestrate neuronal activity throughout the brain to strongly sculpt behavioral functions. Surprising parallelism between the behavioral effects of 5-HT and eCB activity has been widely reported, including the regulation of emotional states, stress homeostasis, cognitive functions, food intake and sleep. The distribution pattern of the 5-HT system and the eCB molecular elements in the brain display a strong overlap and several studies report a functional interplay and even a tight interdependence between eCB/5-HT signaling. In this review, we examine the available evidence of the interaction between the eCB and 5-HT systems. We first introduce the eCB system, then we describe the eCB/5-HT crosstalk at the neuronal and synaptic levels. Finally, we explore the potential eCB/5-HT interaction at the behavioral level with the implication for psychiatric and neurological disorders. The precise elucidation of how this neuromodulatory interaction dynamically regulates biological functions may lead to the development of more targeted therapeutic strategies for the treatment of depressive and anxiety disorders, psychosis and epilepsy.