Efeito do psicodélico 25H-NBOMe sobre o comportamento social em ratos submetidos à neuroinflamação neonatal com lipopolissacarídeo

Abstract

The immune system can modulate the development of the central nervous system during neurodevelopment. In this context, neuroinflammation during the neonatal period has been shown to affect brain development, contributing to several neuronal and behavioral dysfunctions that may manifest throughout life, such as depression, schizophrenia, or autism spectrum disorder. The search for new more effective treatments for neuropsychiatric disorders is constant, and the discovery of new psychotropic substances, such as NBOMe drugs (Nmethoxybenzil), should be investigated for their therapeutic potential, despite their recreational abuse. This study aimed to evaluate the behavioral and protein alterations induced by the administration of lipopolysaccharide (LPS, 0.2 or 1.0 mg/kg, i.p.) in rats in the neonatal period (in a single day or for three consecutive days), and whether these changes can be reversed or attenuated by treatment with 25H-NBOMe. It was observed that LPS decreases the number of ultrasonic vocalizations (VUS) during the first immunological challenge on postnatal day 3 (PND3) but causes the increase of this parameter 2 h after the 3rd application on PND5, when compared to saline. This suggests sickness behavior of prostration initially, followed by resistance or adaptation to LPS with increased communication, or an anxious-like behavior due to the second contact with the test apparatus. However, the communicative alterations were not lasting, as there was no difference between the groups when tested again on PND12. Treatment with LPS also reduced body weight until the prepubescent phase, where a reduction in play behavior was observed in LPS animals compared to saline animals, especially in males exposed to a dose of 1.0 mg/kg for 3 consecutive days, which reduced the number of pouncings and the total, sniffing and following times. In female animals, the differences were more subtle, presenting reductions of the time following and the number of pouncings only. These results did not occur due to lack of locomotor capacity, as there were no statistically relevant differences between saline and LPS animals in the open field test. The protocol for applying LPS in the neonatal period chosen for the continuation of the experiments was the dose of 1.0 mg/kg applied for three consecutive days (PND3-5) because it was the protocol in which the animals presented the most impaired parameters in the social behavior test. When treated with 25H-NBOMe at doses of 0.3 and 1.0 mg/kg, the head twitch response test (HTR) demonstrated that this psychedelic drug was able to increase the frequency of these movements. Regarding play behavior, 25H- NBOMe at a dose of 0.3 mg/kg was able to reverse the decrease in the frequency of pouncings and the total, smelling and following times caused by neonatal inflammation with LPS in maleanimals. However, in saline animals, this same dose reduced 1 the time following and frequency of pouncings, as well as the dose of 1.0 mg/kg, which also reduced the frequency of pinnings in these animals. In female animals, treatment with 25HNBOMe did not alter any parameters of play behavior. Analysis of the expression of GFAP, Iba1 and synaptofisin proteins in the prefrontal cortex revealed no difference caused by neonatal inflammation with LPS nor by treatment with 25H-NBOMe. In conclusion, the study of new drugs and psychotropic substances as potential therapeutic agents in neuropsychiatric disorders needs to be continuously evaluated in order to generate reliable data to find effective and safe doses for clinical studies aimed at treating and managing the symptoms of these disorders.