Mechanisms of the effects of exogenous levodopa on the dopamine-denervatedstriatum

The efficacy of exogenous levodopa (L-DOPA) is attributed to its conversion to dopamine by the enzyme aromatic L-amino-acid decarboxylase in striatal dopaminergic terminals. However, there is controversy about the mechanisms underlying the therapeutic and adverse effects of L-DOPA after almost all s triatal dopaminergic afferents have disappeared (i.e. in the later stages o f Parkinson's disease). After administration of 30 mg/kg or 100 mg/kg of L- DOPA, rats subjected to unilateral dopaminergic denervation showed intense contraversive rotation and a high density of Fos-immunoreactive nuclei thro ughout the denervated striatum, with no significant induction of Fos in the intact striatum. Injection of the central aromatic L-amino-acid decarboxyl ase inhibitor NSD-1015 30 min before and 15 min after the injection of L-DO PA suppressed the rotational behavior and the striatal induction of Fos. Co mparison of results obtained in rats subjected to unilateral and bilateral dopaminergic denervation indicated that the presence of contralateral dopam inergic innervation does not significantly modulate the effects of L-DOPA o n the denervated striatum. Serotonergic denervation led to slight and stati stically non-significant decrease in the rotational behavior and Fos expres sion induced by high doses of L-DOPA (100 mg/kg) in the dopamine-denervated striatum, but totally suppressed the rotational behavior and Fos expressio n induced by low doses of L-DOPA (30 mg/kg). The present data indicate that the major effects observed after administrat ion of exogenous L-DOPA are not due to a direct action of L-DOPA on dopamin e receptors, or to extrastriatal release of dopamine, but to conversion of L-DOPA to dopamine by serotonergic terminals and probably some intrastriata l cells. Given that serotonergic neurons appear to play an important role i n the action of L-DOPA in the later stages of Parkinson's disease, strategi es targeting the serotonergic system should be considered for the treatment of Parkinson's disease and for combating undesirable side effects of L-DOP A therapy. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights res erved.