D5 (not D1) dopamine receptors potentiate burst-firing in neurons of the subthalamic nucleus by modulating an L-type calcium conductance.
Dopamine is a crucial factor in basal ganglia functioning. In current models of basal ganglia, dopamine is postulated to act on striatal neurons. However, it may also act on the subthalamic nucleus (STN), a key nucleus in the basal ganglia circuit. The data presented here were obtained in brain slices using whole-cell patch clamp. They reveal that D5 dopamine receptors strengthen electrical activity in the subset of subthalamic neurons endowed with burst-firing capacity, resulting in longer discharges of spontaneous or evoked bursts. To distinguish between D1 and D5 subtypes, the action of agonists in the D1/D5 receptor family was first investigated on rat subthalamic neurons. Single-cell reverse transcription-PCR profiling showed that burst-competent neurons only expressed D5 receptors. Accordingly, receptors localized in postsynaptic membranes within the STN were labeled by a D5-specific antibody. Second, agonists in the D1/D5 family were tested in mouse brain slices. It was found that these agonists were active in D1 receptor knock-out mice in a similar way to wild-type mice or rats. This proved that D5 rather than D1 receptors were involved. Pharmacological tools (dihydropyridines, omega-conotoxins, and calciseptine) were used to identify the target of D5 receptors as an L-type channel. This was reached via G-protein and protein kinase A. The action of dopamine on D5 receptors therefore shapes neuronal activity. It contributes to normal information processing in basal ganglia outside striatum. This finding may be useful in drug therapy for various disorders involving changes in STN activity, such as Parkinson's disease and related disorders.
Baufreton
Jérôme
J
Signalisation Normale et Pathologique, Unité Mixte de Recherche 5543, Université Victor Segalen, 33076 Bordeaux Cedex, France.
Garret
Maurice
M
Rivera
Alicia
A
de la Calle
Adélaïda
A
Gonon
François
F
Dufy
Bernard
B
Bioulac
Bernard
B
Taupignon
Anne
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050641:Receptors, Dopamine D5; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020531:Subthalamic Nucleus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018491:Dopamine Agonists; C493606:Drd5 protein, mouse; C493607:Drd5 protein, rat; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D026902:Potassium Channel Blockers; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins