Presynaptic CB1 cannabinoid receptors control frontocortical serotonin and glutamate release – Species differences

Both the serotonergic and endocannabinoid systems modulate frontocortical glutamate release; thus they are well positioned to participate in the pathogenesis of psychiatric disorders. With the help of fluorescent and confocal microscopy, we localized the CB1 cannabinoid receptor (CB1R) in VGLUT1- and 2- (i.e. glutamatergic) and serotonin transporter- (i.e. serotonergic) -positive fibers and nerve terminals in the mouse and rat frontal cortex.CB1R activation by the synthetic agonists, WIN55212-2 (1 μM) and R-methanandamide (1 μM) inhibited the simultaneously measured evoked Ca2+-dependent release of [14C]glutamate and [3H]serotonin from frontocortical nerve terminals of Wistar rats, in a fashion sensitive to the CB1R antagonists, O-2050 (1 μM) and LY320135 (5 μM). CB1R agonists also inhibited the evoked release of [14C]glutamate in C57BL/6J mice in a reversible fashion upon washout.Interestingly, the evoked release of [14C]glutamate and [3H]serotonin was significantly greater in the CB1R knockout CD-1 mice. Furthermore, CB1R binding experiments revealed similar frontocortical CB1R density in the rat and the CD-1 mouse. Still, the evoked release of [3H]serotonin was modulated by neither CB1R agonists nor antagonists in wild-type CD-1 or C57BL/6J mice.Altogether, this is the first study to demonstrate functional presynaptic CB1Rs in frontocortical glutamatergic and serotonergic terminals, revealing species differences.

► CB1Rs have high density in three layers of the frontal cortex of the rat and mouse.
► CB1Rs are present in frontocortical glutamatergic and serotonergic nerve terminals.
► CB1R activation decreases evoked glutamate release in rat and mouse synaptosomes.
► CB1R activation decreases serotonin release in rat frontocortical synaptosomes.
► Evoked glutamate and serotonin release is greater in the CB1R KO versus WT mice.