THE EFFECT OF LONG-TERM INTRANASALLY DELIVERED SEROTONIN TREATMENT OF MALE RATS WITH THE NEONATAL DIABETES MELLITUS
ON THE ACTIVITY OF HYPOTHALAMIC SIGNALING SYSTEMS
I.B. Sukhov, K.V. Derkach, O.V. Chistyakova, V.M. Bondareva, A.O. Shpakov 1
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg, 194223;
1 e-mail: alex_shpakov@list.ru
In the type 2 diabetes mellitus (T2DM) the functions of brain serotonin system are attenuated, leading to
metabolic and hormonal dysfunctions. One of the approaches for the correction of the brain serotonin system is
to increase the serotonin level in the central nervous system. The objective of this work was to study the effect
of a five-week treatment of male rats with the neonatal T2DM model by intranasally administered serotonin
(IS) at a daily dose of 20 µg/rat on metabolic parameters and functional activity of adenylyl cyclase signaling
system (ACSS) sensitive to biogenic amines and peptide hormones in the hypothalamus of diabetic animals.
The neonatal model of T2DM was induced by streptozotocin (70 mg/ kg) treatment of five-day rats. At the age
of 4 months the animals with typical signs of T2DM were divided into two groups, with IS treatment (DIS,
n = 6) and without it (D0, n = 6). The IS treatment of diabetic rats restored the regulation of ACSS with the agonists
of type 2 dopamine receptor (DA2R) and of type 4 melanocortin receptor (MC4R), and enhanced the inhibitory
effect of serotonin on adenylyl cyclase activity. One of the main causes of this was the increase in the expression
of genes encoding DA2R, MC4R and subtype 1B 5-hydroxytryptamine receptor (5-HT1BR). In the DIS
group the relationship between the signaling cascades involving different types of serotonin (Gs-coupled
5-HT4,6,7R/Gi-coupled 5-HT1R), dopamine (DA1R/DA2R) and melanocortin (MC3R/MC4R) receptors, which
are responsible for the regulation of ACSS, was also changed. Along with the restoration of hypothalamic hormonal
regulation, the IS treatment improved glucose tolerance and increased insulin sensitivity. The findings
suggest that the prospects of this approach providing the increase of serotonin level in the central nervous system
to restore hypothalamic signaling pathways and metabolic abnormalities dependent on them in T2DM.
Key words:
serotonin, type 2 diabetes mellitus, hypothalamus, adenylyl cyclase system, dopamine receptor,
melanocortin receptor
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