SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB 1 receptors

Background and Purpose Src homology 3‐domain growth factor receptor‐bound 2‐like endophilin interacting protein 1 (SGIP1) interacts with cannabinoid CB 1 receptors. SGIP1 is abundantly and principally expressed within the nervous system. SGIP1 and CB 1 receptors co‐localize in axons and presynaptic boutons. SGIP1 interferes with the internalization of activated CB 1 receptors in transfected heterologous cells. Consequently, the transient association of CB 1 receptors with β‐arrestin2 is enhanced and prolonged, and CB 1 receptor‐mediated ERK1/2 signalling is decreased. Because of these actions, SGIP1 may modulate affect, anxiety, pain processing, and other physiological processes controlled by the endocannabinoid system (ECS). Experimental Approach Using a battery of behavioural tests, we investigated the consequences of SGIP1 deletion in tasks regulated by the ECS in SGIP1 constitutive knockout (SGIP1 −/− ) mice. Key Results In SGIP1 −/− mice, sensorimotor gating, exploratory levels, and working memory are unaltered. SGIP1 −/− mice have decreased anxiety‐like behaviours. Fear extinction to tone is facilitated in SGIP1 −/− females. Several cannabinoid tetrad behaviours are altered in the absence of SGIP1. SGIP1 −/− males exhibit abnormal behaviours on Δ 9 ‐tetrahydrocannabinol withdrawal. SGIP1 deletion also reduces acute nociception, and SGIP1 −/− mice are more sensitive to analgesics. Conclusion and Implications SGIP1 was detected as a novel protein associated with CB 1 receptors, and profoundly modified CB 1 receptor signalling. Genetic deletion of SGIP1 particularly affected behavioural tests of mood‐related assessment and the cannabinoid tetrad. SGIP1 −/− mice exhibit decreased nociception and augmented responses to CB 1 receptor agonists and morphine. These in vivo findings suggest that SGIP1 is a novel modulator of CB 1 receptor‐mediated behaviour.