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 CBI 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 mu M) and R-methanandamide (1 mu M) inhibited the simultaneously measured evoked Ca2+-dependent release of [C-14]glutamate and [H-3]serotonin from frontocortical nerve terminals of Wistar rats, in a fashion sensitive to the CBIR antagonists, 02050 (1 mu M) and LY320135 (5 mu M). CB1R agonists also inhibited the evoked release of [C-14]glutamate in C57BL/6J mice in a reversible fashion upon washout. Interestingly, the evoked release of [C-14]glutamate and [H-3]serotonin was significantly greater in the CBIR 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 [H-3]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 CB(1)Rs in frontocortical glutamatergic and serotonergic terminals, revealing species differences. (c) 2012 Elsevier Ltd. All rights reserved.