Dopamine D4 receptors inhibit depolarization-induced [3H]GABA release in the rat subthalamic nucleus.
We explored the role of dopamine D4 receptors on [3H]GABA release in the subthalamic nucleus. [3H]GABA release was evoked by high K+ in slices of the nucleus. The selective dopamine D4 receptor agonist PD168,077 (N-[[4-(2-cyanophenyl)-1-piperazynil]methyl]-3-methyl-benzamide) inhibited GABA release with greater potency (EC50=3.2 nM) than quinpirole (EC50=200 nM). SKF 21297 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide), a dopamine D1-like receptor agonist, had no effect. L-745,870 (3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1-1H-pyrollo[2,3-b] pyridine), a selective dopamine D4 receptor antagonist, reverted the quinpirole inhibition with greater potency (IC50=8.7 nM) than that of the dopamine D2/D3 receptor antagonist sulpiride and raclopride (IC50=4804 and 788 nM, respectively). Both methylphenidate and methamphetamine, dopamine reuptake blockers, inhibited by 30% high K(+)-evoked GABA release; the inhibition was blocked by L-745,870. These results show that dopamine D4 receptors modulate GABA release in the subthalamic nucleus. The results would explain how agents that increase interstitial dopamine like methylphenidate and amphethamine might control locomotor hyperactivity seen in disorders of dopamine D4 receptors.
Floran
Benjamín
B
Departamento de Fisiología, Biofísica y Neurociencias, CINVESTAV-IPN, México, Mexico.
Floran
Leonor
L
Erlij
David
D
Aceves
Jorge
J
D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008694:Methamphetamine / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D050638:Receptors, Dopamine D4; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D013469:Sulpiride / Q000494:pharmacology; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; C493601:Drd4 protein, rat; D011725:Pyridines; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D014316:Tritium; D050638:Receptors, Dopamine D4; D008774:Methylphenidate; D019257:Quinpirole; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid; D013469:Sulpiride; D011188:Potassium