Cannabinoid CB1 receptor modulation of rod-cone gap junctional coupling in day and night depends on dopamine D₄ receptor activation

Abstract

Purpose : Rods and cones, which are connected by gap junctions, express both cannabinoid 1 receptors (CB1Rs) and dopamine D₄Rs (Yazulla, 2008). Studies of goldfish, rabbit and mouse retinas have shown that the retinal circadian clock lowers dopamine release at night so that D₄Rs are NOT activated, thereby increasing intracellular cAMP, which opens rod-cone gap junctions. Conversely, the clock increases dopamine release and D₄R activation in the day, thereby decreasing cAMP, which closes the gap junctions (Ribelayga et al., 2008; Ribelayga, Mangel, 2010). Although dopamine release is about 3x greater in the day than at night, the extent of rod-cone tracer coupling is ~600x larger at night than in the day; injecting neurobiotin tracer into a single goldfish cone results in its diffusion into 2 nearby rods in the day, but into 1,200 rods at night. We therefore studied whether 1) CB1Rs modulate rod-cone coupling in the day and night and 2) an interaction between cone D₄Rs and CB1Rs increases the day/night difference in rod-cone coupling.

Methods : Intact goldfish neural retinas were studied in the dark in the day and night 1) with and without SR141716A (blocks endogenous CB1R activation), and 2) with a combination of SR141716A and spiperone (D₄R antagonist). Whole cell recording was used to monitor cone responses to dim light (scotopic) stimuli (to determine whether cones are receiving rod input), and to inject neurobiotin into single cones (to determine the extent of rod-cone tracer coupling).

Results : Our data show that SR141716A application alone in the day increased both rod input to cones (i.e., cones began to respond to very dim scotopic stimuli) and the extent of rod-cone tracer coupling. Conversely, SR141716A application alone at night or SR141716A application in the day following 30-min spiperone application decreased both rod input to cones (i.e., cones ceased responding to dim stimuli) and rod-cone tracer coupling.

Conclusions : These results show that endogenous activation of cone CB1Rs decreases rod-cone coupling in the day when D₄Rs are activated but increases it at night when D₄Rs are not activated. These findings thus suggest that the effects of endogenous CB1R activation depend on endogenous D₄R activation, which switches CB1R G-protein signaling from Gs at night to Gi in the day, thereby enhancing the day/night difference in rod-cone coupling.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.