Effect of haloperidol on brain mitochondrial respiration and nitric oxide and superoxide production

S. LORES ARNAIZ; M.F. CORONEL; A. BOVERIS

Santa Bárbara, California, USA

Congreso; Annual Meeting of the Oxigen Club of California; 1998

Oxigen Club of California

Haloperidol, a widely used neuroleptic drug, causes a variety of neurological side effects including various movement disorders. It has been suggested that inhibition of mitochondrial respiration and free radical induction may be involved in haloperidol neurotoxicity. In this study, mice were injected i.p. according to two different treatments: a) a single injection (1 mg/kg), sacrificed 1 hour after the injection (single-dose model), and b) two injections (1 mg/kg each) at 10 a.m and 4 p.m. sacrificed 24 hours after the first dose (double-dose model). Determinations of oxygen consumption were carried out in isolated mitochondria, in the presence of either malate-glutamate or succinate (state 4) and the same substrates plus ADP (state 3). Superoxide and nitric oxide production were measured in submitochondrial particles (SMP). Single-dose haloperidol treatment produced a 33% inhibition in malate-glutamate-dependent respiration rate (state 4), one hour after drug injection. No significant changes were found in malate-glutamate-dependent oxygen consumption after 24 hours (double-dose treatment). No changes were observed in succinate-supported respiration rates of mitochondria from treated mice, as compared with controls. Superoxide production in the presence of NADH and rotenone was increased by 248% in brain SMP from single-dose treated mice (control value: 5.0 ± 0.5 nmol/min.mg protein). Nitric oxide production was inhibited by 39% and 54% in SMP from haloperidol-treated mice (single- and double-dose treatments, respectively) (control value: 1.6 ± 0.2 nmol/min.mg protein). Our results suggest that haloperidol neurotoxicity would be mediated by inhibition of mitochondrial electron transfer and enhancement of superoxide production at the NADH dehydrogenase site. This inhibition does not seem to be caused by increased ONOO- formation.