A mechanism underlying dopamine D1 and D2 receptor-mediated inhibition of dopaminergic neurones in the ventral tegmental area in vitro.
1. An intracellular recording study was performed to elucidate the mechanism underlying D1 and D2 receptor-mediated inhibition of neuronal activities of dopaminergic neurones in the ventral tegmental area (VTA) using slice preparations of the rat brain. 2. VTA neurones were classified into type I and type II neurones according to the shape of the action potential, which correspond to dopaminergic and non-dopaminergic neurones, respectively. 3. Addition of dopamine (10 microM) and quinpirole (1-100 microM) to the bath hyperpolarized the membrane of the type I neurones concomitantly with an increase in membrane conductance and an inhibition of action potentials which occurred spontaneously and were elicited by depolarizing pulses applied to the cell. However, quinpirole (10 microM) had no effect on the threshold for action potentials induced by a depolarizing pulse. 4. These quinpirole (10 microM)-induced effects were antagonized by simultaneous application of domperidone (5 microM), a D2 receptor antagonist. 5. The amplitude of quinpirole (10 microM)-induced hyperpolarization was decreased by increasing the potassium concentration in the perfusing fluid or simultaneous application of tetraethylammonium (10 microM). 6. SKF 38393 (10 or 100 microM), a D1 receptor agonist, had no effect on the resting membrane potential or action potential firing induced by a depolarizing pulse applied to the cell. However, when SKF 38393 (10 microM) was applied simultaneously with quinpirole (10 microM), the threshold for action potential generation was elevated by 5-6 mV, although there was no enhancement of hyperpolarization induced by quinpirole. 7. The elevation of the threshold for action potentials induced by SKF 38393 in the presence of quinpirole was antagonized by simultaneous application of SCH 23390 (5 microM), a D1 receptor antagonist.8. Dopamine (10 microM), quinpirole (10 or 100 microM) and SKF 38393 (10 or 100 microM) had no effect on the resting membrane potential or spontaneously occurring action potentials in type II neurones.9. These findings suggest that activation of dopamine D2 receptors of dopaminergic neurones in the VTA increases potassium conductance, thereby hyperpolarizing the membrane and eventually inhibiting neuronal activities. They also suggest that simultaneous activation of both D1 and D2 receptors enhances the D2 receptor-mediated inhibitory effects by elevation of the threshold for action potential generation.
Momiyama
T
T
Department of Pharmacology, Faculty of Medicine, Kyoto University, Japan.
Todo
N
N
Sasa
M
M
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004294:Domperidone / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D066298:In Vitro Techniques; D007478:Iontophoresis; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D019257:Quinpirole; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013681:Tegmentum Mesencephali / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D001552:Benzazepines; D015259:Dopamine Agents; D004873:Ergolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013757:Tetraethylammonium Compounds; D019257:Quinpirole; D004294:Domperidone; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D011188:Potassium; D004298:Dopamine