Real-time dynamics of dopamine released from neuronal transplants in experimental Parkinson's disease.
Intrastriatal transplantation of foetal midbrain dopamine (DA) neurons ameliorates the fundamental symptoms of dopaminergic denervation in clinical and experimental parkinsonism despite providing only restricted reinnervation. To understand how DA function is restored by these grafts we used fast-scan cyclic voltammetry at a carbon-fiber microelectrode in vitro to monitor directly and in "real time" the dynamics of graft-derived DA. Simulations of Michaelis-Menten kinetics were used to model the experimental observations. We show that the concentration of DA released by a single depolarizing pulse is significantly lower in grafted than intact striata. On the other hand, the extracellular lifetime of DA in grafts is extended due to a marked reduction in the rate maximum (V(max)) for DA reuptake by the DA transporter. Moreover, variations in V(max) and release occur in parallel: where DA release is lowest, V(max) is lowest and vice versa. The consequences of these dynamics are twofold. First, during repeated depolarization at a physiological firing frequency, when net extracellular concentrations reflect DA release versus uptake, ambient levels of extracellular DA within the graft are restored to normal. Second, the protracted extracellular lifetime of DA will increase the number and extracellular sphere of its postsynaptic actions. This effect will be most prominent where DA availability (and thus V(max)) is most restricted. Thus, these data demonstrate that dopaminergic grafts restore striatal dopaminergic function with extracellular dynamics of DA that are different from those of intact striatum but which can normalize ambient DA levels and permit transmission over an extended sphere.
Cragg
S J
SJ
Department of Pharmacology, University of Oxford, United Kingdom.
Clarke
D J
DJ
Greenfield
S A
SA
D000818:Animals; D016380:Brain Tissue Transplantation; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D007700:Kinetics; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000601:surgery; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation*
D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D016627:Oxidopamine; C043425:vanoxerine; D004298:Dopamine