NITRIC-OXIDE REGULATION OF METHAMPHETAMINE-INDUCED DOPAMINE RELEASE IN CAUDATE-PUTAMEN

A possible role for NO modulation of dopamine (DA) release in the caud ate/putamen (CPU) during methamphetamine (METH) exposure was investiga ted using in vivo microdialysis in rats. Inclusion of the nitric oxide synthase (NOS) inhibitors N-G-nitro-L-arginine (NOARG), N-G-nitro-L-a rginine methyl ester (L-NAME) or D-NAME (less potent inhibitor) in the microdialysis buffer prior to METH minimally affected basal levels of DA, DOPAC or HVA in CPU microdialysate. However, L-NAME and NOARG pro duced concentration-dependent decreases of up to 64% (100 mu M) in CPU DA levels in microdialysate during exposure to four doses of METH (5 mg/kg i.p./2 h), with lesser effects on DOPAC or HVA. Reversal of the NOARG inhibition was produced by inclusion of 500 mu M of either L-arg inine or L-citrulline in the microdialysate. D-NAME (100 mu M) minimal ly affected levels of DA or metabolites. Paradoxically, inclusion of f rom 20 to 2 mu M of the NOx generators isosorbide dinitrate (ISON) or sodium nitroprusside (SNP) in the microdialysis buffer decreased DA an d DOPAC levels in microdialysate during METH exposure. This paradox mi ght result from the concentrations of NOx produced by SNP or ISON bein g great and not regionally specific resulting in inhibition of DA rele ase and/or synthesis while the NO generated endogenously during METH e xposure may have localized and site-specific actions. Alternatively, N Ox may inhibit NOS or other enzymes in the NO synthesis pathway, there by reducing levels of an intermediate (other than NO) which potentiate s DA release. In their entirety, our results indicate that NO generati on in the CPU may augment the release of DA during METH exposure.