The Role of the AgRP 25-51 Active Fragment in the Regulation of Functional Activity of Locus Coeruleus Norepinephrinergic Neurons and in Norepinephrine Biosynthesis

Double fluorescence immunolabeling and confocal microscopy showed that the nerve processes immediately surrounding norepinephrinergic (NE) neurons in the brainstem locus coeruleus (LC) are immunopositive to AgRP (agouti gene-related protein), and that NE neurons express melanocortin receptor type 3, but not 4, on their bodies. These findings suggest that the active AgRP 83–132 fragment is able to directly affect NE neurons. In C57BL/6J mice, 3 h after the injection of the AgRP 25–51 fragment (whose action is not mediated by G protein-coupled melanocortin receptors) into the LC, it exhibited an inhibitory effect on NE neurons. The immunolabeling of LC neurons revealed no changes in the level of tyrosine hydroxylase phosphorylated at serine-40, but a significant decrease in levels of tyrosine hydroxylase phosphorylated at serine-31 and dopamine-β-hydroxylase. Real-time PCR showed that after AgRP 25–51 injection, there was a significant decrease in levels of tyrosine hydroxylase mRNA, norepinephrine transporter mRNA, and mRNA of GABA biosynthesis enzymes GAD65/67. HPLC demonstrated that after AgRP 25–51 injection into the LC, the NE level in the striatum and orbitofrontal cortex, i.e. main targets of LC NE neurons, also decreased. The article discusses the mechanisms of interaction of the melanocortin system with LC NE neurons.