The antipsychotics olanzapine, risperidone, clozapine, and haloperidol are D2-selective ex vivo but not in vitro.
In a recent human [(11)C]-(+)-PHNO positron emission tomography study, olanzapine, clozapine, and risperidone occupied D2 receptors in striatum (STR), but, despite their similar in vitro D2 and D3 affinities, failed to occupy D3 receptors in globus pallidus. This study had two aims: (1) to characterize the regional D2/D3 pharmacology of in vitro and ex vivo [(3)H]-(+)-PHNO binding sites in rat brain and (2) to compare, using [(3)H]-(+)-PHNO autoradiography, the ex vivo and in vitro pharmacology of olanzapine, clozapine, risperidone, and haloperidol. Using the D3-selective drug SB277011, we found that ex vivo and in vitro [(3)H]-(+)-PHNO binding in STR is exclusively due to D2, whereas that in cerebellar lobes 9 and 10 is exclusively due to D3. Surprisingly, the D3 contribution to [(3)H]-(+)-PHNO binding in the islands of Calleja, ventral pallidum, substantia nigra, and nucleus accumbens was greater ex vivo than in vitro. Ex vivo, systemically administered olanzapine, risperidone, and haloperidol, at doses occupying approximately 80% D2, did not occupy D3 receptors. Clozapine, which also occupied approximately 80% of D2 receptors ex vivo, occupied a smaller percentage of D3 receptors than predicted by its in vitro pharmacology. Across brain regions, ex vivo occupancy by antipsychotics was inversely related to the D3 contribution to [(3)H]-(+)-PHNO binding. In contrast, in vitro occupancy was similar across brain regions, independent of the regional D3 contribution. These data indicate that at clinically relevant doses, olanzapine, clozapine, risperidone, and haloperidol are D2-selective ex vivo. This unforeseen finding suggests that their clinical effects cannot be attributed to D3 receptor blockade.
McCormick
Patrick N
PN
Institute of Medical Science, University of Toronto, Toronto, ON, Canada. patrick.mccormick@camhpet.ca
Kapur
Shitij
S
Graff-Guerrero
Ariel
A
Raymond
Roger
R
Nobrega
José N
JN
Wilson
Alan A
AA
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography / Q000379:methods; D001569:Benzodiazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D000077152:Olanzapine; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D018967:Risperidone / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics; D010837:Vitamin K 1 / Q000031:analogs & derivatives / Q000493:pharmacokinetics
C510195:2-phytyl-1,4-naphthoquinone; D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D014316:Tritium; D001569:Benzodiazepines; D010837:Vitamin K 1; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine
Nucl Med Biol. 2008 Jan;35(1):11-7
18158938
J Med Chem. 2005 Jun 2;48(11):3663-79
15916415
Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
8935801
Nature. 1990 Sep 13;347(6289):146-51
1975644
Drug Discov Today. 2005 Jul 1;10(13):917-25
15993811
Biol Psychiatry. 2006 Mar 1;59(5):389-94
16373068
J Med Chem. 2005 Jun 16;48(12):4153-60
15943487
Biol Psychiatry. 1993 Feb 15;33(4):227-35
8097114
J Pharmacol Exp Ther. 1994 Jan;268(1):417-26
8301582
Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8155-9
1518841
Arch Gen Psychiatry. 2000 Jun;57(6):553-9
10839333
Synapse. 2009 Sep;63(9):782-93
19489048
Neuropsychopharmacology. 1998 Apr;18(4):305-16
9509498
J Pharmacol Exp Ther. 2003 May;305(2):625-31
12606608
Arch Gen Psychiatry. 2009 Jun;66(6):606-15
19487625
Eur J Pharmacol. 2008 May 6;585(1):130-6
18378227
Brain Res. 1998 Aug 3;800(2):269-74
9685676
Arch Gen Psychiatry. 1992 Jul;49(7):538-44
1352677
Synapse. 2006 Dec 1;60(7):485-95
16952157
J Cereb Blood Flow Metab. 1993 Jan;13(1):24-42
8380178
Synapse. 1994 Jul;17(3):167-72
7974199
FEBS Lett. 1992 Nov 9;312(2-3):123-6
1330688
J Cereb Blood Flow Metab. 1996 Jan;16(1):42-52
8530554
Brain Res Bull. 1982 Jul-Dec;9(1-6):321-53
6816390
Synapse. 2009 Nov;63(11):998-1009
19598174
J Med Chem. 2002 Dec 19;45(26):5727-35
12477356
Histochem J. 1996 Nov;28(11):791-9
8968731
Nucl Med Commun. 2000 Dec;21(12):1113-8
11200015
Eur J Neurosci. 1993 Feb 1;5(2):145-53
8261096
J Med Chem. 2000 Jul 27;43(15):2871-82
10956195
J Pharmacol Exp Ther. 1994 Jan;268(1):495-502
8301592
Synapse. 2000 Aug;37(2):95-103
10881030
J Cereb Blood Flow Metab. 2001 Nov;21(11):1342-53
11702049
J Cereb Blood Flow Metab. 1998 Sep;18(9):941-50
9740097
Am J Psychiatry. 1999 Feb;156(2):286-93
9989565
Brain Res. 1979 Oct 19;175(2):191-217
314832
J Cereb Blood Flow Metab. 2007 Apr;27(4):857-71
17033687
Eur J Pharmacol. 1996 Dec 19;317(2-3):417-23
8997630
Eur J Pharmacol. 1992 Aug 6;218(2-3):373-5
1425949
Am J Psychiatry. 1995 Oct;152(10):1444-9
7573582
J Neurochem. 2006 May;97(4):1089-103
16606355