Tese
Estudo de processos inflamatórios em modelo experimental de adicção induzida por cocaína e nicotina
Fecha
2021-11-30Autor
Magda Luciana de Paula Rosa
Institución
Resumen
Substance use disorder (addiction) is a chronic illness characterized by an inability to regulate
drug-seeking behavior. The release of dopamine in the nucleus accumbens is known to be
essential for the enhancing effects of cocaine. Nicotine also stimulates the mesolimbic
dopaminergic system (reward system) which plays an important role in drug seeking. Studies
have shown that the use of these drugs can interfere with the production and release of
cytokines, suggesting a relationship between inflammation and addiction. Understanding this
relationship can be important in the search for new therapeutic targets and treatment
development. Thus, the present study aimed to investigate the role of inflammatory mediators
and neurotrophic factors in a behavioral model of conditioned place preference (CPP), induced
by the administration of cocaine and nicotine, in mice. Initially, two apparatuses that differed
by the number of compartments were tested. Cocaine-induced conditioning was demonstrated
in both. However, brain levels (prefrontal cortex, hippocampus and striatum) of cytokines and
neurotrophic factors (IL-1β, IL-6, IL-10, TNF-α, CX3CL1, BDNF, GDNF and NGF) were
different depending on the number of compartments in each apparatus. In general, the levels
were found to be increased in the saline groups conditioned in the three-compartment apparatus,
when compared to the same group conditioned in the two-compartment apparatus, suggesting
that the choice of apparatus to be used in CPP studies may influence the research results. When
comparing the saline and cocaine groups, conditioned in the three-compartment apparatus, the
cocaine group showed a reduction in the levels of IL-1β, IL-6, IL-10, GDNF in the prefrontal
cortex and CX3CL1 in the striatum. The experiments to analyze the levels of inflammatory
mediators and neurotrophic factors in mice subjected to nicotine-induced CPP were performed
in a three-compartment apparatus. Increased peripheral levels of IL-6 and IL-10, increased NGF
levels and decreased GDNF in the hippocampus were observed in mice treated with nicotine.
In the striatum there was a decrease in the levels of IL-1β, IL-10 and GDNF. Subsequently,
treatment with clavulanic acid (CA) in cocaine-conditioned animals was analyzed. The doses
of CA used did not prevent cocaine conditioning, when administered thirty minutes before the
drug injections or when administered in a three-day pre-treatment. Possibly, the mechanisms
involved in the increase of GLT-1 expression by CA should require more days of pretreatment.
These results provide evidence for the role of cytokines and neurotrophic factors in cocaine-
and nicotine-induced CPP. Therapeutic strategies can be developed with an understanding of
inflammatory and neurotrophic mechanisms related to addiction in a behavioral model of
location-conditioned preference.