Dopamine receptor occupancy in vivo: measurement using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) inactivates a variety of monoamine neurotransmitter receptors. In this report, protection against EEDQ-induced inactivation of D-1 and D-2 DA receptors by DA antagonists and agonists was used to obtain a measure of occupancy of these receptors in vivo by such drugs. Rats were pretreated with drugs and then given EEDQ (10 mg/kg, i.p.). Twenty-four hours after the EEDQ injections, the animals were decapitated and the number of receptors remaining was measured using conventional receptor binding assays. The D-1 antagonist SCH 23390 potently protected D-1 sites from EEDQ-induced inactivation in a dose-dependent manner. Similarly, NO-756, another D-1 antagonist, selectively protected D-1 sites from inactivation. Conversely, haloperidol, a relatively selective D-2 antagonist, protected D-2 sites from inactivation. Likewise, a number of antipsychotic DA antagonists also protected D-2 sites from inactivation. Clozapine, fluperlapine, and (+) butaclamol were effective at protecting both D-1 sites and D-2 sites. In addition, the D-1 agonist SKF 38393 protected D-1 sites from EEDQ-induced inactivation, whereas the D-2 agonist quinpirole protected D-2 sites. (-) Apomorphine, a mixed D-1/D-2 agonist, protected both sites. Thus, this type of method provides a simple means of evaluating the occupation of DA receptors by DA antagonists and agonists in vivo.
Saller
C F
CF
ICI Pharmaceuticals Group, Wilmington, DE 19897.
Kreamer
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LD
Adamovage
L A
LA
Salama
A I
AI
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004873:Ergolines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D019257:Quinpirole; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000032:analysis; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2
D001552:Benzazepines; D004873:Ergolines; D011804:Quinolines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; C000470:EEDQ; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D003024:Clozapine; D006220:Haloperidol