GPR35 is an orphan receptor expressed in astrocytes and neurons of the central nervous system (CNS), including the hippocampus; however, its role in cognitive functions is largely unknown. This study administered intra-hippocampal injections of GPR35 compound-10 (GPR35C10; a GPR35-selective agonist), ML194 (a GPR35-selective antagonist), and the combination of both to elucidate their pharmacological actions in the Barnes maze. Compared to the vehicle (10 % DMSO) and ML194 groups, animals treated with GPR35C10 showed a higher latency and longer distance to solve the maze (p < 0.05) (an effect prevented by pretreatment with ML194). GPR35C10 increased immobility, suggesting an anxiogenic effect, and decreased average speed compared to the vehicle and ML194 groups (p < 0.05); both actions were prevented by pretreatment with ML194. In the spatial memory test, both the vehicle and ML194 groups showed a preference for the target quadrant (i.e., the quadrant with the tunnel escape) compared with non-target quadrants (p < 0.05). No preference was detected among quadrats in the GPR35C10 group. ML194 prevented the above memory impairment. Regarding the navigation strategies, no differences were detected among treatments in the serial strategy. Animals from the GPR35C10 group showed an increased use of random-strategy compared to the vehicle and ML194 groups (p < 0.05). Animals from the ML194 group exhibited an increased use of spatial strategy compared to the GPR35C10 and combination groups (p < 0.05). Our results suggest that pharmacological stimulation of hippocampal GPR35 interferes with spatial learning, memory, and navigation, and seems to modulate anxiety.
