Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats.
The differential behavioral and neurochemical effects of exogenous L-DOPA in animals with intact versus dopamine (DA)-denervated striata raise questions regarding the role of DA terminals in the regulation of dopaminergic neurotransmission after administration of exogenous L-DOPA. In vivo microdialysis was used to monitor the effect of exogenous L-DOPA on extracellular DA in intact and DA-denervated striata of awake rats. In intact striatum, a small increase in extracellular DA was observed after administration of L-DOPA (50 mg/kg i.p.) but in DA-denervated striatum a much larger increase in extracellular DA was elicited. Additional experiments assessed the role of high-affinity DA uptake and impulse-dependent neurotransmitter release in the effect of exogenous L-DOPA on extracellular DA in striatum. Pretreatment with GBR-12909 (20 mg/kg i.p.), a selective DA uptake inhibitor, enhanced the ability of L-DOPA to increase extracellular DA in intact striatum. However, in DA-denervated striatum, inhibition of DA uptake did not alter the extracellular DA response to L-DOPA. Impulse-dependent neurotransmitter release was blocked by the infusion of tetrodotoxin (TTX; 1 microM), an inhibitor of fast sodium channels, through the dialysis probe. Application of TTX significantly attenuated the L-DOPA-induced increase in extracellular DA observed in striatum of intact rats pretreated with GBR-12909. In a similar manner, TTX infusion significantly attenuated the increase in extracellular DA typically observed in striatum of 6-OHDA-lesioned rats after the administration of L-DOPA. The present results indicate that DA terminals, via high-affinity uptake, play a crucial role in the clearance of extracellular DA formed from exogenous L-DOPA in intact striatum. This regulatory mechanism is absent in the DA-denervated striatum. In addition, this study has shown that DA synthesized from exogenous L-DOPA primarily is released by an impulse-dependent mechanism in both intact and DA-denervated striatum. The latter result suggests an important role for a nondopaminergic neuronal element in striatum that serves as the primary source of extracellular DA formed from exogenous L-DOPA.
Miller
D W
DW
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102, USA.
Abercrombie
E D
ED
D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D016627:Oxidopamine; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013566:Sympathomimetics; D013779:Tetrodotoxin / Q000494:pharmacology
D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D013566:Sympathomimetics; D013779:Tetrodotoxin; D007980:Levodopa; D016627:Oxidopamine; C043425:vanoxerine; D004298:Dopamine