The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor (GPR40) for medium-to-long-chain free fatty acids. Previous studies on the expression of FFAR1 revealed that the nigrostriatal region is one of the areas which express abundant FFAR1 mRNA/protein in the central nervous system (CNS). However, the role of FFAR1 in the CNS has been still largely unclarified. Here, we examined a possible functional role of FFAR1 in the control of extracellular concentrations of striatal monoamines and cocaine-induced locomotor activity. Microdialysis analysis revealed that the basal level of extracellular dopamine (DA) was significantly elevated, while the basal serotonin (5-HT) level tended to be reduced in the striatum of FFAR1 knockout (−/−) mice. Interestingly, local application of a FFAR1 agonist, GW9508, markedly augmented the striatal 5-HT release in FFAR1 wild-type (+/+) mice, whereas topical application of a FFAR1 antagonist, GW1100, significantly reduced the 5-HT release. However, the enhanced 5-HT release was completely lost in −/− mice. Although acute administration of cocaine enhanced the locomotor activity in both +/+ and −/− mice, the magnitude of the enhancement was significantly reduced in −/− mice. In addition, intraperitoneal injection of GW1100 significantly decreased the cocaine-induced locomotor enhancement. These results suggest that FFAR1 has a facilitatory role in striatal 5-HT release, and the evoked 5-HT release might contribute to enhance cocaine-induced locomotor activity.

The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor for medium-to longchain free fatty acids. We have previously demonstrated that FFAR1 is found to be expressed on noradrenergic and serotonergic neurons in the locus coeruleus and rostral ventromedial medulla (RVM), respectively, and local application of a FFAR1 agonist, GW9508, into these areas evokes a descending endogenous pain control system. These results suggest that one of the functions of FFAR1 in the CNS might control central monoaminergic system. Thus, to further pursue this hypothesis in this study, we have tested whether FFAR1 plays a role in the regulation of striatal monoamine release. We also analyzed cocaine-induced locomotor stimulation activity in both FFAR1-/-mice and mice treated with a FFAR1 antagonist to evaluate functional significance of FFAR1. Furthermore, we evaluated possible involvement of FFAR1 signaling in the development of negative emotional behaviors after peripheral inflammation and nerve injury in mice. Our data support that FFAR1 signaling is involved in an important mechanism underlying negative emotional behaviors in the inflammatory and neuropathic pain conditions, and enhancement of FFAR1system may be a new strategy to manage at least comorbid pain and negative emotions.