The preferential nNOS inhibitor 7-nitroindazole and the non-selective one NG-nitro-l-arginine methyl ester administered alone or jointly with l-DOPA differentially affect motor behavior and monoamine metabolism in sham-operated and 6-OHDA-lesioned rats

Abstract

Reciprocal interactions between nitrergic and dopaminergic systems play a key role in the control of motor behavior. In the present study, we performed a comparative analysis of motor behavior (locomotor activity, catalepsy, rotational behavior) and monoamine metabolism in the striatum and substantia nigra of unilaterally sham-operated and 6-OHDA-lesioned rats treated with the preferential neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) or the non-selective one NG-nitro-l-arginine methyl ester (l-NAME), alone or in combination with l-DOPA. Each NOS inhibitor given alone (50mg/kg) induced a distinct catalepsy 30min after injection but only 7-NI impaired spontaneous locomotion after 10min. In 6-OHDA-lesioned rats, chronic l-DOPA (25mg/kg) induced 2.5-h long contralateral rotations. 7-NI (30 and 50mg/kg) markedly reduced the intensity of l-DOPA-induced contralateral rotations while extending their duration until 4.5h whereas l-NAME (50 and 100mg/kg) only tended to attenuate their intensity without affecting the duration. 7-NI but not l-NAME significantly increased endogenous tissue DA levels in the nigrostriatal system of both sham-operated and 6-OHDA-lesioned rats. In l-DOPA-treated group, 7-NI significantly enhanced the l-DOPA-derived tissue DA content in this system and decreased the level of the intracellular DA metabolite DOPAC produced by monoamine oxidase (MAO). In contrast to 7-NI, l-NAME decreased markedly DA content and did not affect DOPAC level in the ipsilateral striatum. It means that the differences in 7-NI and l-NAME-mediated modulation of l-DOPA-induced behavioral and biochemical effects resulted not only from the inhibition of NOS activity but also from differences in their ability to inhibit MAO.