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.