Cannabinoid CB1 receptors and ligands in vertebrate retina: Localization and function of an endogenous signaling system

Abstract

CB1, a cannabinoid receptor enriched in neuronal tissue, was found in high concentration in retinas of rhesus monkey, mouse, rat, chick, goldfish, and tiger salamander by using a subtype-specific polyclonal antibody. Immunolabeling was detected in the two synaptic layers of the retina, the inner and outer plexiform layers, of all six species examined. In the outer plexiform layer, CB1 was located in and͞or on cone pedicles and rod spherules. Labeling was detected in some amacrine cells of all species and in the ganglion cells and ganglion cell axons of all species except fish. In addition, sparse labeling was found in the inner and͞or outer segments of the photoreceptors of monkey, mouse, rat, and chick. Using GC͞MS to detect possible endogenous cannabinoids, we found 3 nmol of 2-arachidonylglycerol per g of tissue, but no anandamide was detectable. Cannabinoid receptor agonists induced a dramatic reduction in the amplitude of voltage-gated L-type calcium channel currents in identified retinal bipolar cells. The presence and distribution of the CB1 receptor, the large amounts of 2-arachidonylglycerol found, and the effects of cannabinoids on calcium channel activity in bipolar cells suggest a substantive role for an endogenous cannabinoid signaling system in retinal physiology, and perhaps vision in general. Cannabinoids are the principal psychoactive component of marijuana and hashish, acting on an intrinsic G proteincoupled receptor in nervous tissue that normally responds to endogenous ligands such as anandamide (arachidonylethanolamide, or AEA) (1). Despite considerable recent progress, the mechanisms of cannabinoid action in the body remain poorly understood, particularly in the case for the role of cannabinoids in vision. Published research and case studies as well as a host of anecdotal reports describe numerous effects on visual perception including altered thresholds of light detection and glare recovery (2-4). The possible loci within the retina and͞or brain responsible for these perceptual changes are unknown. Our report may identify one of the major sites responsible for the alterations in the visual world of some cannabinoid users.The first cannabinoid receptor, CB1, was cloned in 1990 (5). Since then the CB1 receptor has been found to be expressed at high levels in specific brain regions (6). Putative endogenous ligands have been identified: anandamide (1) and 2-arachidonylglycerol (2-AG) (7). Endogenous cannabinoids have been shown to produce effects on memory, signaling pathways, and the perception of pain, (8-14) and have even been found to inhibit dopamine release in the leech (15), implying an inveterate history as a neuromodulatory system. Recent evidence suggests that cannabinoid receptors are found in the retina, with one study demonstrating an anandamide-induced inhibition of dopamine release (16) and another study showing expression of CB1 mRNA through in situ labeling in embryonic rat retina (17). Recently, Porcella et al. (18) have found mRNA for CB1 in retina, by using reverse transcr...

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

“…Inhibition of LTCCs by WIN 55,212-2 has been reported also in identified retinal bipolar cells [20] and in cerebral vascular smooth muscle cells [21]. In the latter case, WIN 55,212-2 and the endocannabinoid anandamide inhibited the LTCCs in a voltage-independent manner and the effects were PTX-sensitive.…”

Synaptic transmission at retinal ribbon synapses

“…RT-PCR and in situ hybridization indicate the presence of both CB1 and CB2 receptors throughout the retina (Lu et al, 2000;Buckley et al, 1998;Porcella et al, 2000). CB1 receptor antibodies label many neurons in the retina, including rod and cone terminals (Straiker et al, 1999;Yazulla et al, 1999;Straiker and Sullivan, 2003). Although the endogenous cannabinoid, anandamide, has not been detected, the CB1 agonist 2-arachidonylglycerol and CB2 agonist palmitoylethanolamide were found to be present in high levels in retina (Straiker et al, 1999).…”

“…CB1 receptor antibodies label many neurons in the retina, including rod and cone terminals (Straiker et al, 1999;Yazulla et al, 1999;Straiker and Sullivan, 2003). Although the endogenous cannabinoid, anandamide, has not been detected, the CB1 agonist 2-arachidonylglycerol and CB2 agonist palmitoylethanolamide were found to be present in high levels in retina (Straiker et al, 1999). Fatty acid amide hydrolase, which hydrolyzes anandamide and 2-arachidonylglycerol, is also widespread in retina and prominently expressed in horizontal cells (Yazulla et al, 1999).…”

GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus

“…Interestingly, a strikingly similar localization of CB1 was recently shown in the retina of different vertebrate species as well. 42 I. Katona et al 802 …”