Receptor subtypes involved in the presynaptic and postsynaptic actions of dopamine on striatal interneurons.
By stimulating distinct receptor subtypes, dopamine (DA) exerts presynaptic and postsynaptic actions on both large aspiny (LA) cholinergic and fast-spiking (FS) parvalbumin-positive interneurons of the striatum. Lack of receptor- and isoform-specific pharmacological agents, however, has hampered the progress toward a detailed identification of the specific DA receptors involved in these actions. To overcome this issue, in the present study we used four different mutant mice in which the expression of specific DA receptors was ablated. In D1 receptor null mice, D1R-/-, DA dose-dependently depolarized both LA and FS interneurons. Interestingly, SCH 233390 (10 microm), a D1-like (D1 and D5) receptor antagonist, but not l-sulpiride (3-10 microm), a D2-like (D2, D3, D4) receptor blocker, prevented this effect, implying D5 receptors in this action. Accordingly, immunohistochemical analyses in both wild-type and D1R-/- mice confirmed the expression of D5 receptors in both cholinergic and parvalbumin-positive interneurons of the striatum. In mice lacking D2 receptors, D2R-/-, the DA-dependent inhibition of GABA transmission was lost in both interneuron populations. Both isoforms of D2 receptor, D2L and D2S, were very likely involved in this inhibitory action, as revealed by the electrophysiological analysis of the effect of the DA D2-like receptor agonist quinpirole in two distinct mutants lacking D2L receptors and expressing variable contents of D2S receptors. The identification of the receptor subtypes involved in the actions of DA on different populations of striatal cells is essential to understand the circuitry of the basal ganglia and to develop pharmacological strategies able to interfere selectively with specific neuronal functions.
Centonze
Diego
D
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy.
Grande
Cristina
C
Usiello
Alessandro
A
Gubellini
Paolo
P
Erbs
Eric
E
Martin
Ana B
AB
Pisani
Antonio
A
Tognazzi
Nadia
N
Bernardi
Giorgio
G
Moratalla
Rosario
R
Borrelli
Emiliana
E
Calabresi
Paolo
P
D000818:Animals; D000918:Antibody Specificity; D015153:Blotting, Western; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004594:Electrophysiology; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011954:Receptors, Dopamine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050641:Receptors, Dopamine D5; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
D018491:Dopamine Agonists; C493606:Drd5 protein, mouse; D020033:Protein Isoforms; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; C113776:dopamine D2L receptor; D050641:Receptors, Dopamine D5; D004298:Dopamine