Differential effect of quinpirole and 7-OH-DPAT on the spontaneous [(3)H]-dopamine efflux from rat striatal synaptosomes.
The effect of quinpirole and 7-OH-DAPT, two D(2)-like agonists, were examined using superfused rat striatal synaptosomes to study the autoregulation of spontaneous [(3)H]-dopamine ([(3)H]-DA) release. Basal [(3)H]-DA efflux was Ca(2+)-dependent by approximately 45% and was inhibited by cadmium 10 microM by 24%. Quinpirole (1 nM to 3 microM) inhibited spontaneous [(3)H]-DA efflux in a concentration-dependent manner (pEC(50) = 7.56 +/- 0.07 and E(max) = 26 +/- 0.09%) and this effect was competitively antagonized by haloperidol (0.3-1 nM) (apparent pA(2) = 9.61 +/- 0.08). In addition, activation of the D(2) DA autoreceptor by quinpirole only modulates the calcium-dependent component of [(3)H]-DA efflux. Low concentrations of a putative-selective D(3) DA agonist, (+/-)-7-OH-DPAT (0.03-0.1 microM), inhibited spontaneous [(3)H]-DA release by 13% (P < 0.05), but higher drug concentrations (> or =1 microM) increased basal [(3)H]-DA efflux in a concentration-dependent, nonsaturable, but reversible manner. Haloperidol (1-10 nM) reversed the (+/-)-7-OH-DPAT-induced inhibition, but not the increase in [(3)H]-DA outflow. The effect of (+/-)-7-OH-DPAT was mimicked by (+)-7-OH-DPAT. However, another putative D(3) DA agonist, PD 128,907 (1 nM to 3 microM), decreased spontaneous tritium efflux (maximal inhibition of 19 +/- 3.06% at 3 microM, P < 0.01). The effect of 7-OH-DPAT 10 microM was independent of the presence of extracellular Ca(2+), since its effect on basal [(3)H]-DA outflow was not significantly modified in a 200 nM free-Ca(2+) medium. In addition, the 7-OH-DPAT-induced enhancement of basal [(3)H]-DA efflux does not involve depolarization of nerve terminals or the reversal of the DA uptake system, as tetrodotoxin (1 microM) and nomifensine (1microM) did not modify the effect of 7-OH-DPAT 10 microM. The present data indicate that activation of D(2) DA autoreceptor subtype by quinpirole inhibits Ca(2+)-dependent spontaneous [(3)H]-DA efflux. 7-OH-DPAT activates the D(2) DA autoreceptor at low concentrations, whereas its action in releasing [(3)H]-DA effect is not receptor-mediated and could involve other mechanisms other than either conventional vesicular exocytosis or the DA uptake system.
García-Sanz
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A
Departament de Farmacologia i Terapèutica, Facultat de Medicina, Univeristat Autònoma de Barcelona, Barcelona, Spain.
Badia
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A
Clos
M V
MV
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000493:pharmacokinetics*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
D001578:Benzopyrans; D015220:Calcium Channels; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; D014316:Tritium; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D019257:Quinpirole; D013779:Tetrodotoxin; D006220:Haloperidol; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D002118:Calcium; D004298:Dopamine