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. 2010 Jul;35(8):1826-35.
doi: 10.1038/npp.2010.50. Epub 2010 Apr 21.

The antipsychotics olanzapine, risperidone, clozapine, and haloperidol are D2-selective ex vivo but not in vitro

Patrick N McCormick  1 , Shitij Kapur, Ariel Graff-Guerrero, Roger Raymond, José N Nobrega, Alan A Wilson
Affiliations

The antipsychotics olanzapine, risperidone, clozapine, and haloperidol are D2-selective ex vivo but not in vitro

Patrick N McCormick et al. Neuropsychopharmacology. 2010 Jul.

Abstract

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.

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Figures

Figure 1
Figure 1
In vitro affinity (pKi) of various antipsychotic drugs for cloned dopamine D2 and D3 receptors (human and rat). None of the drugs shown here display >fourfold selectivity for D2 over D3 receptors. Data are from the National Institutes of Mental Health (NIMH) Psychoactive Drug Screening Program (PDSP) Ki database located at http://pdsp.cwru.edu/pdsp.asp and references therein. The number of individual values included in the average D2 and D3 affinities, respectively, are quetiapine 17, 10; remoxipride 8, 7; clozapine 33, 20; olanzapine 19, 12; loxapine 13, 4; ziprazidone 7, 5; risperidone 24, 13; chlorpromazine 19, 10; and haloperidol 39, 22. Radioligands used in determination of Ki values were [3H]-raclopride, [3H]-nemonapride, [125I]-iodosulpiride, [3H]-spiperone, or [3H]-N-methylspiperone.
Figure 2
Figure 2
Typical control [3H]-(+)-PHNO autoradiographs in rat brain measured ex vivo (left) and in vitro (right). The anterior–posterior coordinate (anterior to bregma) is shown to the right of each autoradiograph. Regions of interest at each coordinate are 1.60 mm, cerebral cortex (CRT), striatum (STR), nucleus accumbens (NACC), islands of Calleja (ICJ); −0.3 mm, STR, ventral pallidum (VP); −5.2 mm, substantia nigra (SN); −12.7 mm, cerebellar cortex (CER), cerebellar lobes 9 and 10 (LOB).
Figure 3
Figure 3
Regional [3H]-(+)-PHNO binding in striatum (STR), nucleus accumbens (NACC), cerebellar lobes 9 and 10 (LOB), substantia nigra (SN), and cerebral cortex (CRT), measured ex vivo in vehicle-treated rats (top) and in vitro in control brain sections (bottom). To facilitate direct visual comparison between ex vivo and in vitro [3H]-(+)-PHNO binding, only those brain regions examined in both the ex vivo and in vitro conditions are shown on the main horizontal axis. Ex vivo binding in islands of Calleja (ICJ) are shown in the inset of the top graph (note difference in scale). Note also that in vitro STR binding, as opposed to that in the other regions, was measured in two tissue sections per slide resulting in a total of 10 separate measurements.
Figure 4
Figure 4
Ex vivo (left) and in vitro (right) SB277011 and antipsychotic occupancy in cerebellar lobes 9 and 10 (LOB), ventral pallidum (VP), islands of Calleja (ICJ, ex vivo condition only), nucleus accumbens (NACC), and striatum (STR). Dashed lines indicate the 0 and 80% occupancy levels. Note the similarity in STR occupancy both between antipsychotic drugs and between the ex vivo and in vitro conditions. Note also the similarity in LOB occupancy for SB277011 ex vivo vs in vitro. *p<0.05, **p<0.001 significant occupancy (ie significant reduction in [3H]-(+)-PHNO binding relative to control group); ##p<0.01, ### p<0.001 occupancy significantly different from ex vivo condition.
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