Efeitos neuroquímicos no sistema colinérgico e dopaminérgico do uso da vareniclina em um modelo animal de exposição à fumaça do cigarro durante a adolescência

Abstract

Smoking is currently considered the leading cause of preventable death in the world. Although several countries are showing a significant drop in the number of users, the use of tobacco products is still a major public health problem worldwide. Nicotine is the main substance present in tobacco leaves, being widely identified as responsible for the development of dependence. Unfortunately, the habit of smoking starts during adolescence for most users, and this is one of the reasons pointed out as responsible for chronic use throughout adulthood, generating numerous long-term damages. However, pharmacotherapeutic approaches are initiated only in adulthood due to the scarcity of information about the effects of using these drugs during adolescence. Varenicline, a partial agonist drug of α4β2 and total of α7 nicotinic cholinergic receptors, is one of the drugs approved for the treatment of nicotine-associated substance use disorder for adults. In the present study, this substance was used in the treatment of an animal model of exposure to cigarette smoke during adolescence with the objective of evaluating its effects on neurochemical parameters. From postnatal day 30 (PN30) to 45, 93 Swiss mice (both sexes) were exposed to cigarette smoke (0.73 mg nicotine; FUM) or air (AR) for 8 h/day in automated exposure. In PN41, treatment with varenicline (0.5 mg/kg/bid p.o.; VAR) or water (AG) was started; from PN46 to PN56, the dose was doubled. One part of the animals was euthanized at PN41 (before treatment with varenicline) and the other at PN56 (after treatment). Chronic exposure to cigarette smoke for eleven days (PN41) did not affect the levels of alfa-4, alfa-7 and beta-2 subunits of cholinergic receptors, and the enzyme tyrosine hydroxylase (TH) and dopamine transporter protein (DAT) in the hippocampus of adolescent animals. Treatment with varenicline for fifteen days after exposure to smoke increased levels of the alfa-4 subunit, but not beta-2, in the hippocampus of adolescent females. Varenicline down-regulated the alfa-7 subunit in the hippocampus of animals previously exposed to cigarette smoke. Varenicline did not affect TH levels in the hippocampus of any of the experimental groups, even after fifteen days of treatment. Treatment with varenicline attenuated DAT levels in the hippocampus in both sexes. Exposure to cigarette smoke and treatment with varenicline altered DAT levels in the hippocampus of males but not females. Our results indicate that, although the use of varenicline is safe, this drug has a sex-dependent effect on the dopamine neurochemical circuitry in adolescent animals. These findings indicate that the study of the effects of the use of varenicline in the treatment of adolescent smokers should be deepened