Presynaptic cannabinoid CB2 receptors modulate [³H]‐Glutamate release at subthalamo‐nigral terminals of the rat

Abstract

Recent studies suggested the expression of CB2 receptors in neurons of the CNS, however, most of these studies have only explored one aspect of the receptors, i.e., expression of protein, messenger RNA, or functional response, and more complete studies appear to be needed to establish adequately their role in the neuronal function. Electron microscopy studies showed the presence of CB2r in asymmetric terminals of the substantia nigra pars reticulata (SNr), and its mRNA appeared is expressed in the subthalamic nucleus. Here, we explore the expression, source, and functional effects of such receptors by different experimental approaches. Through PCR and immunochemistry, we showed mRNA and protein for CB2rs in slices and primary neuronal cultures from subthalamus. GW833972A, GW405833, and JHW 133, three CB2r agonists dose-dependent inhibited K -induced [ H]-Glutamate release in slices of SNr, and the two antagonist/inverse agonists, JTE-907 and AM630, but not AM281, a CB1r antagonist, prevented GW833972A effect. Subthalamus lesions with kainic acid prevented GW833972A inhibition on release and decreased CB2r protein in nigral synaptosomes, thus nigral CB2rs originate in subthalamus. Inhibition of [ H]-Glutamate release was PTX- and gallein-sensitive, suggesting a Gi -mediated effect. P/Q Ca -type channel blocker, ω-Agatoxin-TK, also inhibited the [ H]-Glutamate release, this effect was occluded with GW833972A inhibition, indicating that the βγ subunit effect is exerted on Ca channel activity. Finally, microinjections of GW833972A in SNr induced contralateral turning. Our data showed that presynaptic CB2rs inhibit [ H]-Glutamate release in subthalamo-nigral terminals by P/Q-channels modulation through the Gi subunit and suggested their participation in motor behavior.

Cellular Distribution of Canonical and Putative Cannabinoid Receptors in Canine Cervical Dorsal Root Ganglia

“…The expression of faint CB 2 receptor immunolabeling in neurons and its absence in SGCs of canine DRG, partially agrees with previous findings in laboratory rodents, where only very weak immunoflorescence was found in basal conditions (56). Although CB 2 receptor was considered lacking in neurons and glial cells, recent literature highlights its expression in these cell types (57, 58), even in humans (54) and dogs (11, 59). Similarly to CB 1 (28), CB 2 receptor is upregulated in a variety of PNS and CNS diseases and is suggested as a promising pharmacological target in the management of chronic pain and neuroinflammation (29–31, 56).…”

Differential ultrastructural alterations in the Vglut2 glutamatergic input to the substantia nigra pars compacta/pars reticulata following nigrostriatal dopamine loss in a progressive mouse model of Parkinson’s disease

“…Although there are no direct data supporting this later hypothesis, it is possible that there is differential localization of various presynaptic receptors on Vglut2+ terminals within the SNpc versus SNpr that could variably regulate the release of glutamate. It has been reported that there are various presynaptic receptors located on STN terminals, such as the cannabinoid (Sánchez‐Zavaleta et al., 2018) and GABA (Wu, Song, Faull, & Waldvogel, 2018), making it possible that these receptors are differentially distributed within various neurons of the STN.…”

Early Consumption of Cannabinoids: From Adult Neurogenesis to Behavior

“…Their activation inhibits the activity of adenylate cyclase and stimulates the protein kinase activated by mitogenesis (MAPK) as well as phosphoinositide 3-kinase (PI3K). Both receptors are distributed in the presynapses of both excitatory and inhibitory neurons, inhibiting voltage-regulated Ca 2+ channels and inhibiting the vesicular release of neurotransmitters such as γ-aminobutyric acid (GABA) and glutamate [ 17 , 18 , 25 ]. This cannabinoid-mediated response is a retrograde inhibitory signaling system that plays an important role in maintaining homeostasis in the CNS [ 26 , 27 ].…”

“…This makes sense, as the neurogenic process has been described to be a tightly regulated process [ 65 , 66 ]; for that reason, a strong stimulus may be necessary to disrupt this regulation. Additionally, it should be noted that the ECS is strongly associated with the modulation of GABAergic and glutamatergic neurotransmission [ 17 , 18 , 25 ]. Therefore, these synaptic mechanisms may participate in the neurogenic effect reported for CB1/CB2 stimulation.…”