Neurotoxicity of dopamine and protective effects of the NMDA receptor antagonist AP-5 differ between male and female dopaminergic neurons.
Neurodevelopmental and neurodegenerative disorders related to dopaminergic transmission typically exhibit a sex-specific prevalence. In order to investigate the underlying cellular mechanisms, primary cultures of dissociated embryonic rat midbrain were subject to a 24 h treatment with dopamine in concentrations between 1 and 1000 microM. Dopamine caused a dose-dependent loss of neurons and reduction of neurites immunoreactive to tyrosine hydroxylase with a LD50 of about 100 microM. Application of D1-like or D2-like receptor agonists instead of dopamine did not induce cell loss. Neither D1-like or D2-like receptor antagonists nor the nitric oxide synthase inhibitor N-nitro-L-arginine were capable of blocking dopamine-induced cell death. When tissue from male and female donors was cultured separately, a twofold sex difference was consistently present: (1) Survival rates of female dopaminergic neurons in the presence of LD50 concentrations of dopamine were about twice those of male neurons. (2) The N-methyl-D-aspartate-receptor antagonist AP-5 was capable of rescuing female but not male dopaminergic neurons from dopamine-induced cell death. It is concluded that dopamine neurotoxicity is not mediated by dopamine receptors and is aggravated by glutamate excitotoxicity but not by nitric oxide. The male-specific vulnerability is the first direct evidence that the prevalence of certain neurodevelopmental or neurodegenerative disorders may have a basis in the biology of the single dopaminergic neuron.