D2 dopamine receptors and modulation of spontaneous acetylcholine (ACh) release from rat striatal synaptosomes.
1. The effect of two D3/2 dopamine receptor agonists, LY-171555 (quinpirole) and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on spontaneous [3H]-acetylcholine ([3H]-ACh) release were investigated in rat striatal synaptosomes. 2. Quinpirole and 7-OH-DPAT inhibited in a concentration-dependent manner the basal efflux of [3H]-ACh with similar Emax (maximal inhibitory effect) values (29.95 +/- 2.91% and 33.19 +/- 1.21%, respectively). Significant differences were obtained between the pEC50 (-log of molar concentration) of quinpirole (7.87 +/- 0.12) and 7-OH-DPAT (7.21 +/- 0.17; P < 0.01). 3. Different concentrations (0.3-10 nM) of haloperidol (D2/3 dopamine receptor antagonist) shifted to the right the concentration-response curves elicited by quinpirole and 7-OH-DPAT, without modifications in the Emax. 4. Slopes of a Schild plot obtained with haloperidol in the presence of quinpirole and 7-OH-DPAT were not significantly different from unity (0.85 +/- 0.05 and 1.17 +/- 0.11, respectively) and consequently haloperidol interacted with a homogeneous receptor population. The pKB values of haloperidol obtained from Schild regression were 9.96 +/- 0.15 (in presence of quinpirole) and 9.90 +/- 0.09 (in presence of 7-OH-DPAT). 5. Specific binding of [3H]-YM-09151-2 to membranes of striatal synaptosomes and cells expressing D2 and D3 dopamine receptors was inhibited by haloperidol. Analysis of competition curves revealed the existence of a single population of receptors. There were no differences between the estimated pKi (-log of molar concentration) values for synaptosomes (8.96 +/- 0.02) and cells expressing D2 receptors (8.81 +/- 0.05), but the pKi value from cells expressing D3 dopamine receptors differed significantly (8.48 +/- 0.06; P < 0.01). 6. In conclusion, the data obtained in the present study indicate that quinpirole and 7-OH-DPAT, two D3/2 dopamine receptor agonists, inhibit the spontaneous [3H]-ACh efflux and this effect is competitively antagonized by haloperidol and probably mediated through dopamine D2 receptors.
Clos
M V
MV
Department de Farmacologia i Terapéutica, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
García-Sanz
A
A
Vivas
N M
NM
Badia
A
A
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D001549:Benzamides; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D017661:Receptors, Presynaptic; D013764:Tetrahydronaphthalenes; D019257:Quinpirole; D000109:Acetylcholine; C030265:nemonapride; C031349:7-hydroxy-2-N,N-dipropylaminotetralin