RESUMO
Schizophrenia is a severe mental disorder with numerous etiological susceptibilities. Maternal infection is a key risk factor for schizophrenia. Prenatal lipopolysaccharide (LPS) infection stimulates cytokine production that affects brain development. In the present study, we aimed to investigate the effect of prenatal LPS injection at gestational day (GD) 14-16 on behavioral paradigms, and neuronal morphology in the prefrontal cortex (PFC), basolateral amygdala (BLA), nucleus accumbens (NAcc) and ventral hippocampus (VH) at two critical ages of development: pre-pubertal (postnatal day 35, PD35) and post-pubertal (PD60) age in male rats. We also evaluated the effects of LPS on nitric oxide (NO) and zinc (Zn) levels in seven brain areas (PFC, VH, amygdala, brainstem, striatum and dorsal hippocampus) at PD35 and PD60. LPS induced hyperlocomotion in a novel environment and reduced social contact as well as increased the levels of NO and Zn in the PFC, brainstem and amygdala as observed in other animal models of schizophrenia-related behavior. Furthermore, we found that LPS-treated rats presented post-pubertal neuronal hypertrophy in the PFC and BLA and decreased spine density in the NAcc. The neuronal morphology of neurons in the VH in LPS-treated rats remained unaltered. Interestingly, the anxiogenic-related behavior correlated with neuronal hypertrophy observed in the BLA. Our findings suggest that the behavioral and neural modifications observed in our model could be mediated by the long-lasting alterations in Zn and NO levels in the brain.
Assuntos
Encéfalo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Óxido Nítrico/metabolismo , Zinco/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Encéfalo/imunologia , Estimulantes do Sistema Nervoso Central/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/imunologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/imunologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Ratos Sprague-DawleyRESUMO
Administration of psychostimulants can elicit a sensitized response to the stimulating and reinforcing properties of the drugs, although there is scarce information regarding their effects at immune level. We previously demonstrated that an acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in met-enkephalin at limbic and immune levels, 4 days following drug administration. In this study, we evaluated the amphetamine-induced effects at weeks one and three after the same single dose treatment (5 mg/kg, i.p.) on the lymphoproliferative response and on the met-enkephalin in the nucleus accumbens (NAc), prefrontal cortex (PfC), spleen and thymus. It was demonstrated that these effects disappeared completely after three weeks, although re-exposure to an amphetamine challenge induced the expression of sensitization to the effects of amphetamine on the lymphoproliferative response and on the met-enkephalin from NAc, spleen and thymus, but not in the PfC. Pre-treatment with MK-801 (0.1 mg/kg, i.p.), an N-methyl-d-aspartate (NMDA) glutamatergic receptor antagonist, blocked the effects of a single amphetamine exposure on the lymphoproliferative response and on met-enkephalin in the NAc and spleen. Furthermore, the NMDA receptor antagonist administered prior to amphetamine challenge also blocked the expression of sensitization in both parameters evaluated. These findings show a long-lasting amphetamine-induced sensitization phenomenon at the immune level in a parallel way to that occurring in the limbic and immune enkephalineric system. A glutamate mechanism is implied in the long-term amphetamine-induced effects at immune level and in the met-enkephalin from NAc and spleen.