Effects induced by cannabinoids on monoaminergic systems in the brain and their implications for psychiatric disorders

The endocannabinoid system and CB1 receptors participate in the control of emotional behavior and mood through a functional coupling with the classic monoaminergic systems. In general, the acute stimulation of CB1 receptors increases the activity (spontaneous firing rate) of noradrenergic (NE), serotonergic (5-HT) and dopaminergic (DA) neurons as well as the synthesis and/or release of the corresponding neurotransmitter in specific brain regions. Notably, the antagonist/inverse agonist rimonabant (SR141617A) can decrease the basal activity of NE and 5-HT neurons, suggesting a tonic/constitutive regulation of these neuronal systems by endocannabinoids acting at CB1 receptors. Monoaminergic systems are modulated via CB1 receptors by direct or indirect effects depending on the localization of this inhibitory receptor, which can be present on monoaminergic neurons themselves and/or inhibitory (GABAergic) and/or excitatory (glutamatergic) regulatory neurons. The repeated stimulation of CB1 receptors is not associated with the induction of tolerance (receptor desensitization) on the activity of NE, 5-HT and DA neurons, in contrast to chronic agonist effects on neurotransmitter synthesis and/or release in some brain regions. CB1 receptor desensitization may alter the direct and/or indirect effects of cannabinoid drugs modulating the functionality of monoaminergic systems. The sustained activation of monoaminergic neurons by cannabinoid drugs can also be related to changes in the function of presynaptic inhibitory α2-adrenoceptors or 5-HT1A receptors (autoreceptors and heteroreceptors), whose sensitivity is downregulated or upregulated upon chronic CB1 agonist exposure. The functional interactions between endocannabinoids and monoaminergic systems in the brain indicate a potential role for CB1 receptor signaling in the neurobiology of various psychiatric disorders, including major depression and schizophrenia as the major syndromes.

► The acute stimulation of CB1 receptors modulates monoaminergic systems in the brain.
► Chronic CB1 receptor activation does not induce tolerance on monoaminergic systems.
► CB1 receptors modulate monoaminergic systems by direct or indirect effects.
► CB1 receptor signaling has potential roles in major depression and schizophrenia.