Dopamine release and uptake dynamics within nonhuman primate striatum in vitro.
The putamen of the human striatum is a heterogeneous nucleus that contains the primary site of loss of dopamine (DA) in Parkinson's disease (PD). Furthermore, different functional domains of the putamen are heterogeneously susceptible to DA loss, and yet the dynamic regulation of extracellular DA concentration ([DA](o)) and comparison between domains has not been explored in the primate brain. In these studies, DA was measured in real time using fast-scan cyclic voltammetry at a carbon-fiber microelectrode in vitro in striatal sections from the common marmoset (Callithrix jacchus). [DA](o) released by a single stimulus pulse varied threefold along a ventromedial-dorsolateral axis. DA uptake was via the DA transporter (GBR12909 sensitive, desipramine insensitive). On the basis of data modeling with simulations of Michaelis-Menten kinetics, rate maximum, V(max), varied with region: both [DA](o) and V(max) were greatest in regions most vulnerable in PD. These differences were reflected in part by regional variation in DA content. [DA](o), V(max), and regional variation were two- to threefold greater than in rodent caudatoputamen. In addition, steady-state [DA](o) at physiological firing rates in primate striatum was controlled by depolarization frequency, uptake, and presynaptic autoreceptors. Furthermore, regulation of [DA](o) by these mechanisms differed significantly between limbic- and motor-associated domains. These data indicate interspecies heterogeneity in striatal DA dynamics that must be considered when extrapolating behavioral and drug responses from rodent to the primate brain. Moreover, the heterogeneity demonstrated within the primate putamen in the availability and dynamic regulation of DA may be central to understanding DA function in health, cocaine abuse, and disease.
Cragg
S J
SJ
University Department of Pharmacology, Oxford, OX1 3QT, United Kingdom. stephanie.cragg@pharm.ox.ac.uk
Hille
C J
CJ
Greenfield
S A
SA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002144:Callithrix; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins; D008839:Microelectrodes; D008959:Models, Neurological; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011699:Putamen / Q000737:chemistry / Q000378:metabolism; D012684:Sensory Thresholds / Q000502:physiology; D013045:Species Specificity; D027981:Symporters
D017660:Autoreceptors; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters; D015102:3,4-Dihydroxyphenylacetic Acid; D008274:Magnesium; D002118:Calcium; D004298:Dopamine