RESISTANCE OF NEURONAL NITRIC-OXIDE SYNTHASE-DEFICIENT MICE TO METHAMPHETAMINE-INDUCED DOPAMINERGIC NEUROTOXICITY

Methamphetamine (METH) is a powerful psychostimulant that produces dop aminergic neurotoxicity manifested by a decrease in the levels of dopa mine, tyrosine hydroxylase activity and dopamine transporter (DAT) bin ding sites in the nigrostriatal system. We have recently reported that blockade of the neuronal nitric oxide synthase (nNOS) isoform by 7-ni troindazole provides protection against METH-induced neurotoxicity in Swiss Webster mice. The present study was undertaken to investigate th e effect of a neurotoxic dose of METH on mutant mice lacking the nNOS gene [nNOS(-/-)] and wild-type controls. In addition, we sought to inv estigate the behavioral outcome of exposure to a neurotoxic dose of ME TH. Homozygote nNOS(-/-), heterozygote nNOS(+/-) and wild-type animals were administered either saline or METH (5 mg/kg x 3). Dopamine, DOPA C and HVA levels, as well as DAT binding site levels, were determined in striatal tissue derived 72 h after the last METH injection. This re gimen of METH given to nNOS(-/-) mice affected neither the tissue cont ent of dopamine and its metabolites nor the number of DAT binding site s. Although a moderate reduction in the levels of dopamine (35%) and D AT binding sites (32%) occurred in striatum of heterozygote nNOS(+/-) mice, a more profound depletion of the dopaminergic markers (up to 68% ) was observed in the wild-type animals. METH-induced hyperthermia was observed in all animal strains examined except the nNOS(-/-) mice. In vestigation of the animals' spontaneous locomotor activity before and after administration of the neurotoxic dose of METH (5 mg/kg x 3) reve aled no differences. A low dose of METH (1.0 mg/kg) administered to na ive animals (nNOS(-/-) and wild-type) resulted in a similar intensity of locomotor stimulation. However, 68 to 72 h after exposure to the hi gh-dose METH regimen, a marked sensitized response to a challenge METH injection was observed in the wild-type mice but not in the nNOS(-/-) mice. Taken together, these results indicate that nNOS(-/-) mice are protected against METH-induced dopaminergic neurotoxicity and locomoto r sensitization. It also appears that a partial deficit of dopaminergi c transmission in wild-type animals does not prevent the development o f sensitization to METH, whereas a deficit in nNOS may attenuate this process.