Anxiodepressive state induced by neonatal administration of the dipeptidyl peptidase-IV inhibitors with different mechanisms of action: A model of neurodevelopmental disorder

At present emotional and motivational diseases (including anxiety and depression) are often believed to be neurodevelopmental disorders. Anatomical and functional brain systems responsible for emotional reactions are formed at the second half of pregnancy and early postnatal period, when synaptogenesis of major neurotransmitter systems involved in emotions is realized. Experimental and clinical data testify to the involvement of proline-specific peptidase dipeptidyl peptidase IV (DP-IV, EC 3.4.14.5) in the genesis of anxiety and depressive disorders. In the developing rat brain DP-IV activity increases up to 4th postnatal week and then decreases during maturation. Pharmacological intervention in early ontogeny can affect brain development and cause behavioral alterations in adult animals. In our studies, neonatal rat pups were treated (5–18 postnatal days) with DP-IV inhibitors with different mechanisms of action – non-competitive irreversible inhibitor methionyl-2(S)-cyano-pyrrolidine (1 mg/ kg), competitive high selective inhibitors diprotin A (2 mg/kg) and sitagliptin (4 mg/kg); control rats were treated with saline. At the age of 1, 2, 3 and 6 months experimental rats demonstrated anxiety- and depression-like behavior in the elevated plus maze, forced swimming test, sucrose consumption/preference test and some others. Sitagliptin was the least efficient in the induction of behavioral alterations. Data prove the development of anxiety-depressive state in adolescent and adult rats postnatally exposed to inhibitors of DP-IV. This experimental approach is effective in order to study the development of affective disorders.