Biphasic inhibition of stimulated endogenous dopamine release by 7-OH-DPAT in slices of rat nucleus accumbens.
1. Fast cyclic voltammetry was used to investigate the effect of 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin), a putative D3 receptor agonist, on electrically stimulated endogenous dopamine release in slices of rat nucleus accumbens. 2. 7-OH-DPAT inhibited single pulse stimulated dopamine release in a concentration-dependent manner with a maximum inhibition of 95.5%. Analysis of concentration-response curves to 7-OH-DPAT showed that they were biphasic, with the high affinity component contributing 18.0% to the total inhibition and the low affinity component 77.5%. 7-OH-DPAT exhibited a 560 fold selectivity between the high and low affinity components (0.015 nM compared to 8.4 nM). 3. Concentration-response curves to the non-selective D2/D3 agonist, apomorphine, were monophasic. The maximum inhibition was 93.1% and the EC50 value 82 nM. 4. The selective D2 antagonist, haloperidol (30 nM), antagonized the low affinity component of the concentration-response cuve to 7-OH-DPAT whilst the high affinity component was essentially unaffected. The pKB values calculated for the high and low affinity components were 7.89 and 9.45 respectively. 5. In conclusion, these results demonstrate that 7-OH-DPAT inhibits stimulated dopamine release by acting at two different sites. Furthermore, the results are consistent with the hypothesis that the high and low affinity components of the concentration-response curve to 7-OH-DPAT may reflect activation of functional D3 and D2 release-regulating autoreceptors respectively. However, the possibility that the biphasic nature of the curve may reflect different subtypes of the D2 receptor cannot be excluded.
Patel
J
J
Department of Pharmacology, Queen Mary & Westfield College, London.
Trout
S J
SJ
Palij
P
P
Whelpton
R
R
Kruk
Z L
ZL
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D004563:Electrochemistry; D006220:Haloperidol / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; D006220:Haloperidol; D001058:Apomorphine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D004298:Dopamine