ACETAMINOPHEN (APAP) OVERDOSE DECREASED DOPAMINE LEVELS IN THE MAIN BRAIN AREAS INVOLVED IN LOCOMOTOR REGULATION IN RATS

PERÉZ MJ.; GHANEM CI; VIGO MB; MANAUTOU JE; DEFINO F

Baltimore

Congreso; 56 Annual Meeting and ToxExp; 2017

Society of Toxicology

APAP overdose is theleading cause of acute liver failure (ALF) in the USA. We previously reported a reduction in locomotor activity (~50%) in rats with APAP-induced liver damage, but without ALF. The aim of the present study was to evaluate the effect of acute APAP intoxication on the dopamine (DA) system in brain areas regulating locomotion. For this purpose, male Wistar rats were dosed with APAP (1g/kg) or vehicle. 24h later, pre-frontal cortex (Pfc), N. Accumbens (Ac), striatum (St) and cortex (Cx) were processed to measure DA levels by HPLC. Another cohort of rats was used to evaluate protein expression of a mastrocyte marker (Glial fibrilar protein; Gfap), a neuronal marker (Neurofilament heavy; NF200) and nuclear translocation of Nrf2 as indicator of response to oxidative stress. APAP significantly decreased DA levels in Pfc and St by 80% and 50%, respectively, with no changes detected in Ac or Cx. DOPAC, the main metabolite of DA, was increased by 117% in St, while decreased in Pfc and Ac by 63% and 83%, respectively. GFAP protein expression was significantly increased by 70%, 202% and 9% in St, Ac and Pfc, respectively, with no changes in Cx. By contrast, Nf200 expression significantly decreased 66%, 70% and 39% in Pfc, Ac and St, respectively, with no changes in Cx. APAP also increased nuclear localization of Nrf2 by 150%, 140% and 42% in Pfc Ac and Cx, respectively, with no changes in St. Our results demonstrate that hepatotoxicity by APAP not resulting in ALF occurs concurrently with decreases in DA levels in brain areas involved in locomotor regulation. This suggests that impairment in DA signaling may be responsible for APAP-induced hypolocomotion. We also propose that this response could involve activation of endocannabinoid system by AM404, the principal APAP metabolite in brain. We also demonstrated that APAP produces astrogliosis and a decrease the marker of neurons processes, suggesting neuronal damage too. The absence of ALF in these rats strongly support the idea that these are direct toxic effects of APAP in the brain.