Abstract
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.
Highlights
The free fatty acid receptor 1 (FFAR1) is a G-protein-coupled receptor, which is originally demonstrated to be abundantly expressed in pancreatic β-cells and activated by medium-to-long-chain (C12-C22) free fatty acids (FFAs) (Briscoe et al, 2003; Itoh et al, 2003; Kotarsky et al, 2003; Stoddart et al, 2008; Mancini et al, 2013)
The in vivo microdialysis experiments suggested that FFAR1 directly/indirectly regulated at least striatal DA and 5-HT levels
The main findings of the current study include the following: 1) FFAR1 tonically regulated striatal 5-HT release: activation of FFAR1 facilitated 5-HT release, but inhibition of this receptor downregulated the release, and 2) FFAR1−/− mice and mice treated with the FFAR1 antagonist (GW1100) demonstrated reduced locomotor activity in response to cocaine administration
Summary
The free fatty acid receptor 1 (FFAR1) is a G-protein-coupled receptor ( known as GPR40), which is originally demonstrated to be abundantly expressed in pancreatic β-cells and activated by medium-to-long-chain (C12-C22) free fatty acids (FFAs) (Briscoe et al, 2003; Itoh et al, 2003; Kotarsky et al, 2003; Stoddart et al, 2008; Mancini et al, 2013). We have recently found that the disfunction of FFAR1 signaling contributes to the emotional-related behaviors (Nishinaka et al, 2014; Aizawa et al, 2016; Aizawa et al, 2017; Aizawa et al, 2018) and FFAR1-deficient (FFAR1−/−) mice showed altered monoamine levels in several brain areas including hippocampus, midbrain, hypothalamus, and medulla oblongata (Aizawa et al, 2016) These results suggest that one of the functions of FFAR1 in the CNS might control the central monoaminergic system
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