The CB1 Cannabinoid Receptor Is the Major Cannabinoid Receptor at Excitatory Presynaptic Sites in the Hippocampus and Cerebellum

Abstract

Endocannabinoids work as retrograde messengers and contribute to short-term and long-term modulation of synaptic transmission via presynaptic cannabinoid receptors. It is generally accepted that the CB1 cannabinoid receptor (CB1) mediates the effects of endocannabinoid in inhibitory synapses. For excitatory synapses, however, contributions of CB1, "CB3," and some other unidentified receptors have been suggested. In the present study we used electrophysiological and immunohistochemical techniques and examined the type(s) of cannabinoid receptor functioning at hippocampal and cerebellar excitatory synapses. Our electrophysiological data clearly demonstrate the predominant contribution of CB1. At hippocampal excitatory synapses on pyramidal neurons the cannabinoid-induced synaptic suppression was reversed by a CB1-specific antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), and was absent in CB1 knock-out mice. At climbing fiber (CF) and parallel fiber (PF) synapses on cerebellar Purkinje cells the cannabinoid-dependent suppression was absent in CB1 knock-out mice. The presence of CB1 at presynaptic terminals was confirmed by immunohistochemical experiments with specific antibodies against CB1. In immunoelectron microscopy the densities of CB1-positive signals in hippocampal excitatory terminals and cerebellar PF terminals were much lower than in inhibitory terminals but were clearly higher than the background. Along the long axis of PFs, the CB1 was localized at a much higher density on the perisynaptic membrane than on the extrasynaptic and synaptic regions. In contrast, CB1 density was low in CF terminals and was not significantly higher than the background. Despite the discrepancy between the electrophysiological and morphological data for CB1 expression on CFs, these results collectively indicate that CB1 is responsible for cannabinoid-dependent suppression of excitatory transmission in the hippocampus and cerebellum.

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

“…It is worth mentioning that the CB1 receptor has been shown to be 10-20 times more expressed in inhibitory terminals as compared with excitatory terminals in hippocampus and cerebellar cortex (Kawamura et al, 2006). Thus, another interesting issue is how the huge differences of CB1 receptor expression levels on the two neuronal subpopulations studied here (very high abundance in GABAergic neurons and low abundance in cortical glutamatergic neurons) can explain the differential responses to high and low doses of cannabinoids and the underlying molecular mechanisms discussed above.…”

Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making

“…There are also reports demonstrating CB1Rs localization on glutamatergic axonal ends (Domenici et al 2006;Kawamura et al 2006;Reguero et al 2011) and on astrocytes (Navarrete and Araque 2008) in various brain regions. We thus examined the pattern of distribution of CB1 receptors and colocalization of these receptors with major neuronal populations including GABAergic, glutamatergic, dopaminergic, and serotoninergic neurons and astrocytes in the ACC and OFC.…”

“…It is well established that CB1Rs are localized at GABAergic axonal ends in many brain regions (Bodor et al 2005;Kawamura et al 2006;Matyas et al 2006) including PFC (Chiu et al 2010). There are also reports demonstrating CB1Rs localization on glutamatergic axonal ends (Domenici et al 2006;Kawamura et al 2006;Reguero et al 2011) and on astrocytes (Navarrete and Araque 2008) in various brain regions.…”

Cannabinoids and Epilepsy

“…CB 1 Rs are most densely expressed at cortical and hippocampal presynaptic γ-aminobutyric acid (GABA)ergic presynaptic boutons, especially cholecystokinin-positive (CCK+) and parvalbumin-negative GABAergic interneurons [64][65][66]. Glutamatergic axon terminals in cortical and subcortical neurons contain fewer presynaptic CB1 receptors than GABAergic terminals [65,[67][68][69][70][71].…”