Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics invivo.

Abstract

Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. L-DOPA was introduced as a viable treatment option for PD over 40years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-DOPA administration (50mg/kg carbidopa+0, 100, and 250mg/kg L-DOPA) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry in anesthetized rats. We demonstrate that L-DOPA enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR. In both regions, L-DOPA progressively attenuated reuptake kinetics, predominantly through a decrease in Vmax . These findings have important implications on understanding the pharmacodynamics of L-DOPA, which may be informative for understanding its therapeutic effects and also common side effects like L-DOPA-induced dyskinesias (LID). L-DOPA is commonly used to treat Parkinsonian symptoms, but little is known about how it affects presynaptic DA neurotransmission. Using invivo fast-scan cyclic voltammetry, we show L-DOPA inhibits DA reuptake in a region-specific and dose-dependent manner, and L-DOPA has paradoxical effects on release. These findings may be important when considering mechanisms for L-DOPA's therapeutic benefits and adverse side-effects.