Administration of a synthetic dipeptidyl peptidase IV inhibitor methionyl-2(S)-cyanopyrrolidine (1 mg/kg) to rats during the early postnatal period was followed by the development of behavioral changes in young and adult animals. The degree of anxiety in the elevated plus maze increased in treated rats at the age of 1-2 months. Depressive behavior in the forced swimming test was typical of animals aging 2-3 months. Diazepam reduced the severity of anxiety in treated rats. Melipramine had a normalizing effect on swimming behavior. A novel prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine had the antidepressant properties.

Background: The chronic stress of social isolation is a valid predictor of cognitive pathology. This study aimed to compare the effects of long-term social isolation on female versus male Wistar rats’ learning and memory. We hypothesized that prolonged social isolation stress, which starts early in life, would affect learning in a sex-dependent manner. Methods: Social isolation started at the edge of early to mid-adolescence and lasted 9 months. The rat’s cognitive abilities were assessed by habituation and reactivity to novelty in the open field (OF) test, spatial memory in the Morris water maze (MWM), and the conditioned passive avoidance (PA) reflex. Basal serum corticosterone levels were assessed using an enzyme-linked immunosorbent assay. Results: Regardless of the housing conditions, females habituated to the OF under low illumination slower than males. Under bright light, the single-housed rats showed hyporeactivity to novelty. In the MWM, all the rats learned to locate the platform; however, on the first training day, the single-housed females’ speed was lower relative to other groups. Four months later, in the post-reminder probe trial, the single-housed rats reached the area around the platform site later, and only males, regardless of housing conditions, preferred the target quadrant. Single-housed rats, irrespective of sex, showed a PA deficit. There was a more pronounced conditioned fear in the single-housed males than in females. In both male and female rats, basal corticosterone levels in rat blood serum after 9 months of social isolation did not differ from that in the group-housed rats of the corresponding sex. Meanwhile, females’ basal corticosterone level was higher than in males, regardless of the housing conditions. The relative weight of the adrenal glands was increased only in single-housed females. Conclusions: Under long-term social isolation, started early in life, single-housed females compared with males showed more pronounced cognitive impairments in the MWM and PA paradigm, findings that specify their greater vulnerability to the stress of prolonged social isolation.

Activities of prolyl endopeptidase and dipeptidyl peptidase IV in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus were measured in rats with the experimental anxious-depressive syndrome induced by treatment with a dipeptidyl peptidase IV inhibitor during the early postnatal period (days 5-18). Prolyl endopeptidase activity was elevated in the frontal cortex, hypothalamus, and nucleus accumbens. Increased activity of dipeptidyl peptidase IV was observed in the hypothalamus and striatum. Norepinephrine/serotonin reuptake inhibitor, imipramine, and noncompetitive prolyl endopeptidase inhibitor, benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, were shown to abolish depression-like behavior of animals in the forced swimming test. These compounds had a normalizing effect on activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats.

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Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 -18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A-or sitagliptin-treated rats in the elevated plus maze; diprotin A also enhanced the animals' anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A-and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 -3 months of age. Increased aggression was observed in 1 -3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats' behavior more significantly than sitagliptin when the animals were treated with the DPP-IV

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The development of MPTP-induced depressive syndrome in rats was accompanied by activation of prolyl endopeptidase and dipeptidyl peptidase IV in the brain frontal cortex. Prolyl endopeptidase activity in the striatum also increased under these conditions. Our results indicate that proline-specific peptidases in the target structures of the brain dopaminergic system are involved in the pathogenesis of dopamine deficiency-dependent depressive states.