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The Journal of Neuroscience, July 16, 2003, 23(15):6245-6254
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Receptor Subtypes Involved in the Presynaptic and Postsynaptic Actions of Dopamine on Striatal Interneurons
Diego Centonze,1 Cristina Grande,2 Alessandro Usiello,3 Paolo Gubellini,1 Eric Erbs,3 Ana B. Martín,2 Antonio Pisani,1 Nadia Tognazzi,3 Giorgio Bernardi,1 Rosario Moratalla,2 * Emiliana Borrelli,3 * andPaolo Calabresi1 * 1Clinica Neurologica, Dipartimento di Neuroscienze, Università "Tor Vergata," 00133 Rome, Italy, and Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00179 Rome, Italy, 2Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain, and 3Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique–Institut National de la Santé et de la Recherche Médicale–Université Louis Pasteur, BP 10142, CU de Strasbourg, France
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 µM), a D1-like (D1 and D5) receptor antagonist, but not L-sulpiride (3–10 µM), 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.
Key words: basal ganglia; D1 receptors; D2L receptors; D2S receptors; electrophysiology; GABA transmission; mutant mice
Received Dec. 16, 2002; revised Apr. 24, 2003; accepted Apr. 24, 2003.
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