Potencial terapêutico sexo-dependente da oxitocina em modelos de dependência da nicotina em camundongos adolescentes

Abstract

The number of smokers worldwide has decreased in recent years, being relatively higher among males. However, the tobacco industry has increasingly invested in the modernization of electronic cigarettes (e-cigarettes). Nicotine is the main component present in cigarette smoke, responsible for causing chemical dependence among tobacco users. It influences the mesocorticolimbic dopaminergic reward system and the extended amygdala system. Since the adolescent brain has not yet fully developed all its structures and neural connections, susceptibility to nicotine is greater during this period. Several therapies have been proposed for smoking cessation; however, given their limitations and side effects, new therapeutic targets need to be investigated. Previous studies have shown that the neuropeptide oxytocin (OXT) has the ability to mitigate dependence induced by drugs of abuse. In this context, the present study aims to investigate the effect of OXT administration on behavioral responses associated with nicotine dependence in adolescent mice. To this end, we evaluated the effectiveness of intranasal administration of this neuropeptide on nicotine’s ability to induce behavioral sensitization using the open field test (OF), on anxiety levels after drug withdrawal using the elevated plus maze test (EPM), and on nicotine’s ability to induce conditioning using the conditioned place preference test (CPP). Adolescent male and female Swiss mice were used in this study. These animals were tested on postnatal day 30 (PN30) and postnatal day 40 (PN40) using the OF and EPM tests, respectively, over a 12-day period, referred to as subproject 1. They received intranasal administration of OXT (100 µg/kg) 1 hour before the OF test and an intraperitoneal (i.p.) injection of nicotine (0.5 mg/kg). In the EPM test, they were not exposed to any drugs, i.e., they underwent a 48-hour drug-free period. The animals were also tested on PN30 using the CPP test, referred to as subproject 2. The nicotine and OXT doses used in this test were the same as those used in the OF test. Results showed that nicotine induces behavioral sensitization, which was reversed by OXT administration in females. There were no significant effects or interactions between the drugs regarding anxiety in mice. Nicotine also induced place conditioning; however, this effect was not altered by OXT administration. OXT appears to be a promising molecule for smoking cessation, showing potential in pharmacological therapies by interfering with nicotine’s rewarding properties. Nevertheless, the effects of this neuropeptide are sex-dependent and vary according to the life stage in which it is self-administered. Further studies are needed to clarify the mechanisms underlying OXT’s action in nicotine-induced dependence.