Receptor subtype-specific modulation by dopamine of glutamatergic responses in striatal medium spiny neurons.
ABSTRACT The output of GABAergic medium-sized spiny neurons in the dorsal striatum is controlled in part by glutamatergic input from the neocortex and the thalamus, and dopaminergic input from ventral midbrain. We acutely isolated these neurons from juvenile (P14-24) rats to study the consequences of the interaction between glutamate and dopamine for neuronal excitability. Single-cell RT-PCR analysis was used to identify the expression patterns of dopamine receptors. D1 and D2 dopamine receptor mRNA was detected in 11/22 and 3/22 of isolated neurons, respectively. Receptor mRNA co-expression was detected in 1/22 cells tested. Whole-cell voltage clamp recording (V(h)=-70 mV) was combined with local or bath application of dopaminergic and glutamatergic agonists to explore dopamine receptor modulation of glutamatergic excitation. Glutamate-evoked inward currents (5 microM, Mg(2+)-free, 1 microM glycine) were attenuated by dopamine (5 microM) to 83.2+/-3.6% (n=31). NMDA-evoked (20 microM), APV-sensitive currents were attenuated by dopamine to 80.9+/-4.5% (n=24). NMDA-induced responses were also attenuated by the D1 receptor agonist SKF 38393 (1 microM; n=28), while the D2/3 receptor agonist quinpirole (10 microM) had no effect. The currents evoked by application of AMPA (5 microM) displayed a steady rundown. Application of dopamine abolished or significantly reduced the rundown in the cells tested (n=17). A similar effect was observed after the application of SKF 38393 (1 microM), while quinpirole (10 microM) had no significant effect. Our results provide direct evidence for modulation by dopamine of glutamatergic responses of striatal medium spiny neurons, and demonstrate that the effects of this neuromodulator are receptor subtype specific. Disruption of this modulatory effect is likely to contribute to movement disorders associated with Parkinson's disease.
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ABSTRACT: Electroresponsiveness of neostriatal neurons was studied by intracellular recording in a rat brain slice preparation maintained in standard solution or in solution containing K-channel blockers. In standard solution, the neurons fired repetitively at increasing frequencies with increasing amplitude of direct depolarization. The firing pattern was independent of the membrane potential from which firing was induced. In the presence of tetraethylammonium (20 mM), long-lasting (300-500 ms) plateau potentials could be elicited by the injection of short (5-10 ms) current pulses. Plateau potentials persisted in Na-free solution, in the presence of tetrodotoxin (1-3 microM) and if Ca in the perifusate was replaced by Ba. The plateau was blocked by Cd (500 microM). The plateaux were followed by depolarizing after-potentials. When the plateau potential failed due to fatigue, a small slow depolarization of short duration (10-30 ms) was elicited in Na-free or tetrodotoxin-containing solution, which increased in amplitude with membrane hyperpolarization. This slow depolarization was blocked by Cd, indicating that it was also mediated by Ca. By intrastriatal stimulation in the presence of 4-aminopyridine a long-lasting, voltage-dependent depolarization was triggered from the enhanced postsynaptic potential. In contrast, in the presence of tetraethylammonium, postsynaptic potentials were only slightly increased if they were compared at sizes subthreshold for the plateau potentials. It is concluded that neostriatal neurons, although being characterized as "silent" and "non-bursting", possess slow conductances for inward currents which they share with other mammalian central neurons. However, in contrast, to other central neurons, their Ca-spikes are suppressed by their K-conductances and, in contrast to oscillating neurons, low-threshold Ca-potentials are not prominent.Neuroscience 02/1987; 20(1):293-303. · 3.12 Impact Factor
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ABSTRACT: Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological and biochemical characteristics. The D2 dopamine receptor has been implicated in the pathophysiology and treatment of movement disorders, schizophrenia and drug addiction. The D2 dopamine receptor interacts with guanine nucleotide-binding proteins to induce second messenger systems. Other members of the family of receptors that are coupled to G proteins share a significant similarity in primary amino-acid sequence and exhibit an archetypical topology predicted to consist of seven putative transmembrane domains. We have taken advantage of the expected nucleotide sequence similarities among members of this gene family to isolate genes coding for new receptors. Using the hamster beta 2-adrenergic receptor gene as a hybridization probe we have isolated related genes including a cDNA encoding the rat D2 dopamine receptor. This receptor has been characterized on the basis of three criteria: the deduced amino-acid sequence which reveals that it is a member of the family of G-protein-coupled receptors; the tissue distribution of the mRNA which parallels that of the D2 dopamine receptor; and the pharmacological profile of mouse fibroblast cells transfected with the cDNA.Nature 01/1988; 336(6201):783-7. · 38.60 Impact Factor