4.2 GPR26
GPR26, first cloned in 2000, is a Class A (Rhodopsin) GPCR that couples to Gs and promotes constitutive activation of the adenylyl cyclase (AC) pathway (Jones et al., 2007; Lee et al., 2001). GPR26 is brain-specific, with enriched expression observed within the cortex, amygdala, hippocampus, hypothalamus, thalamus and midbrain ventral tegmental area (VTA)-SN (Ehrlich et al., 2018; Jones et al., 2007; Lee et al., 2001; Zhang et al., 2011). Early studies hypothesized GPR26 to be activated by nucleoside di- and tri-phosphates based on its sequence homology with purinergic P2Y receptors; however, this was not confirmed (Lee et al., 2001) and GPR26 remains orphaned.
GPR26 mRNA and protein are found in several brain regions critical in regulating reward processing including the amygdala and midbrain VTA-SN (Jones et al., 2007). While little research has directly explored the role of GPR26 in alcohol or substance use disorders, using a novel GPR26 KO mouse line, Zhang and colleagues (Zhang et al., 2011) showed male GPR26 KO mice consumed more alcohol than WT controls in a two-bottle free-choice paradigm. However, this was only observed at a low concentration of alcohol (7% v/v), and at higher concentrations (9% and 12% v/v), alcohol-drinking behaviours were similar to WT (Zhang et al., 2011). This same study linked GPR26 to anxiety and depression, two disorders that are often co-morbid with alcohol and other substance use disorders (Boden & Fergusson, 2011; Sinha, 2012; Walker, 2021). GPR26 deficient mice showed heightened levels of anxiety-like behaviour in the elevated plus maze and open field test, and increased depression-like behaviours in the Porsolt swim and tail suspension test (Zhang et al., 2011). However, the links between aberrant anxiety- and depressive-like behaviour and alcohol consumption were not explored. GPR26 KO mice also displayed reduced CREB phosphorylation in the CeA compared to WT counterparts (Zhang et al., 2011), a process that has been linked to heightened anxiety and alcohol consumption (Pandey et al., 2005). However, little future exploration has arisen from these studies, and no novel targeting methods have arisen to further explore the links between GPR26, anxiety, depression and alcohol intake.