Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects

The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB₁) and cannabinoid type 2 (CB₂) receptor and endogenous compounds. The CB₁ receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB₁ receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB₂ receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electrophysiological, neurochemical and behavioural evidences for modulation of the NA/5-HT systems by cannabinoids and the CB₁ receptor. Cannabinoids regulate the neuronal activity of NA and 5-HT cells and the release of NA and 5-HT by direct and indirect mechanisms. The interaction between cannabinoid and NA/5-HT systems may underlie several behavioural changes induced by cannabis such as anxiolytic and antidepressant effects or side effects (e.g. disruption of attention). Further research is needed to better understand different aspects of NA and 5-HT systems regulation by cannabinoids, which would be relevant for their use in therapeutics.