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Domperidone from High-Affinity Sites of the Dopamine D2 Receptor, But

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Domperidone from High-Affinity Sites of the Dopamine D2 Receptor, But SYNAPSE 49:209–215 (2003) Dopamine Displaces [3H]Domperidone From High-Affinity Sites of the Dopamine D2 Receptor, But Not [3H]Raclopride or [3H]Spiperone in Isotonic Medium: Implications for Human Positron Emission Tomography PHILIP SEEMAN,1,2* TERESA TALLERICO,2 AND FRANC¸ OISE KO1 1Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S JA8 2Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada M5S JA8 KEY WORDS high-affinity state of D2; antipsychotics; brain imaging; amphetamine ABSTRACT Because the high-affinity state of the dopamine D2 receptor, D2High, is the functional state of the receptor, has a role in demarcating typical from atypical antipsychotics, and is markedly elevated in amphetamine-sensitized rats, it is important to have a method for the convenient detection of this state by a ligand. The present data show that, in contrast to [3H]spiperone or [3H]raclopride, [3H]domperidone labels D2High sites in the presence of isotonic NaCl in either striatum or cloned D2Long receptors, yielding a dopamine dissociation constant (1.75 nM) in agreement with that found with [3H]dopamine. Increased labeling of D2High sites occurred with [3H]domp- eridone after severe disruption of the cells, suggesting that [3H]domperidone has better access to the D2 receptor from the cytoplasmic aspect of the cell membrane. The density of the [3H]domperidone-labeled D2 receptors was the same as that of the [3H]raclopride- labeled D2 receptors, but twice the density of [3H]spiperone sites for human cloned D2Long receptors, compatible with the monomer-dimer concept of the D2 receptor. [3H]domperidone readily labels the D2High sites in postmortem human brain homoge- nates. Although [3H]spiperone or [3H]raclopride can occupy D2High sites, the inability of 1–10 nM dopamine to displace these ligands under isotonic conditions suggests that these ligands may not be suitable for monitoring the physiological high-affinity state of the dopamine D2 receptor by means of [11C]methylspiperone or [11C]raclopride in hu- mans. Synapse 49:209–215, 2003. © 2003 Wiley-Liss, Inc. INTRODUCTION predominantly (ϳ85–90% of the total population) in The dopamine D2 receptor exists in two states. The the low-affinity state (Seeman et al., 1985; Huff and high-affinity state of the D2 receptor is sensitive to Molinoff, 1982). However, using striatal slices and 3 dopamine concentrations in the 1–10 nM range (al- [ H]spiperone, Richfield et al. (1986) found that 90% of though values of up to 100 nM have been reported). The low-affinity state of the D2 receptor is sensitive to high dopamine concentrations between 100–2,000 nM Contract grant sponsors: NARSAD (the National Alliance for Research on Schizophrenia and Depression), the CIHR (Canadian Institutes of Health Re- (Hamblyn et al., 1984; Watanabe et al., 1985; Grigori- search), NIDA (the National Institute on Drug Abuse), the Stanley Medical adis and Seeman, 1986). Research Institute, the Stanley Scholars Program of the Stanley Medical Re- search Institute, and by donations from Dr. Karolina Jus and the Medland and Although the high-affinity state of the dopamine D2 O’Rorke families, the Grace Lumsden/Margaret Nicholds Graduate Scholarship (to FK). receptor (or D2High) is the functional state of the re- *Correspondence to: Philip Seeman, Department of Psychiatry, 1 King’s Col- ceptor in the anterior pituitary (George et al., 1985), lege Circle, Medical Sciences Building, Room 4344, Toronto, Ontario, Canada D2High has not been widely studied in nervous tissue. M5S JA8. E-mail: [email protected] This is because dopamine competition with the com- Received 30 March 2003; Accepted 21 April 2003 DOI 10.1002/syn.10232 monly used ligands ([3H]spiperone or [3H]raclopride) on homogenized tissues reveal that D2 receptors are © 2003 WILEY-LISS, INC. 210 P. SEEMAN ET AL. the D2-labeled sites were in the high-affinity state, the binding of [3H]spiperone, [3H]raclopride, and with a dopamine dissociation constant of 8.2 nM. [3H]domperidone (Martres et al., 1978; Baudry et al., The clinical relevance of D2High in the nervous sys- 1979; Grigoriadis and Seeman, 1986) to cloned dopa- tem has recently become apparent in several different mine D2 receptors. types of studies. First, the striata from rats sensitized to amphetamine had a normal density of D2 receptors, MATERIALS AND METHODS but revealed a 360% increase in the density of the Frozen rat brains were purchased (Pel-Freez Biologi- D2High sites, compatible with a marked supersensitiv- cals, Rogers, AR) and stored at –70° until used. The ity to dopamine-mimetics (Seeman et al., 2002). brain was partly thawed and the striata removed. The Second, the absolute value of the dopamine dissoci- striata were homogenized in buffer (4 mg frozen tissue ation constant at D2High, 1.75 nM, separates antipsy- per ml buffer) using a Teflon-glass homogenizer with chotic drugs into traditional ones (which typically elicit the piston rotating at 500 rpm and 10 up-and-down parkinsonism) and atypical ones (which elicit little or strokes of the glass container. The buffer contained 50 no parkinsonism) (Seeman, 2002). While this value of mM Tris-HCl (pH 7.4 at 20°), 1 mM EDTA, 5 mM KCl, 1.75 nM was obtained on human cloned D2 receptors, 1.5 mM CaCl2, 4 mM MgCl2, and either 10 mM or 120 the dopamine dissociation constant reported in the lit- mM NaCl (see Results). The homogenate was not 3 erature for D2High ranges from 2 nM (using [ H]raclo- washed, centrifuged, or preincubated because previous pride; Malmberg et al., 1998) to 4.5–229 nM (using work found that more than 30% of the D2 receptors 3 [ H]spiperone; Gru¨ newald et al., 1996; Chio et al., were lost by these procedures (Seeman et al., 1984). 1994; Wiens et al., 1998; Payne et al., 2002) to 22–56 Postmortem human frozen tissues were prepared in 125 nM (using [ I]iodosulpride; Sokoloff et al., 1992; Pera- the same manner as that for the rat tissues. The frozen chon et al., 1999). postmortem human striata were obtained from the Na- Third, although D2High is the physiologically func- tional Neurological Research Specimen Bank (Los An- tional state, it has not been possible to measure the geles, CA). The diagnosis of schizophrenia was taken density or proportion of D2High states by either from the case notes as recorded by the physicians in 11 11 [ C]raclopride or [ C]methylspiperone by means of charge. The frozen human tissues were dissected free positron emission tomography in humans (Aalto et al., of gross myelin tracts, homogenized, and further pro- 2002). cessed as described above for the rat striata. One of the reasons for different dopamine dissocia- We used the human cloned dopamine D2Long recep- tion constants at D2High is that the competition curves tor (in Chinese hamster ovary cells; Liu et al., 2000). 3 3 between dopamine and [ H]spiperone, [ H]raclopride, The cells were harvested by gently scraping the cells off 125 or [ I]iodosulpride do not reveal a clear, unambiguous the bottom of the Petri dish, centrifuged, resuspended high-affinity component which is distinct or separate in phosphate-buffered saline (0.9% NaCl), recentri- from the low-affinity component. That is, the high- and fuged, and the pellet frozen at –70°. When used, the low-affinity components blend into one another and one frozen pellet was thawed and the cells suspended at must use computer-assisted separation of the compo- 200 ␮g protein/ml. The suspension was homogenized nents, with attendant assumptions and limitations, to for 5 sec (Polytron, setting 5), without any further determine the dopamine dissociation constant at washing or centrifugation. D2High (Watanabe et al., 1985). Another reason is that [3H]Raclopride (60–80 Ci/mmol; final concentration the dissociation constant can depend on the ligand of 2 nM in the incubation tube), [3H]spiperone (101 used and on the final concentration of NaCl, despite all Ci/mmol; final concentration of 250 pM), were pur- the appropriate corrections (Watanabe et al., 1985; chased from PerkinElmer Life Sciences (Boston, MA). Seeman and Van Tol, 1995). [3H]Domperidone was custom-synthesized as [phenyl- In addition to the difficulty in determining the true 3H(N)]domperidone (42 Ci/mmol) by PerkinElmer Life dopamine dissociation constant at D2High, there is Sciences and used at a final concentration of 1.2 nM. lack of agreement on the density of dopamine D2 re- The competition between a drug and a [3H]ligand for ceptors as labeled by the various dopaminergic ligands. binding at the receptors was done as follows. Each In particular, the density of [3H]spiperone-labeled D2 incubation tube (12 ϫ 75 mm, glass) received, in the sites has been reported as either equal to the density of following order, 0.5 ml. buffer, 0.25 ml [3H]ligand, and [3H]domperidone-labeled D2 sites (Huff and Molinoff, 0.25 ml of tissue homogenate. The tubes, containing a 1982; Lazareno and Nahorski, 1982) or higher than the total volume of 1 ml, were incubated for2hatroom density of [3H]domperidone-labeled D2 sites (Hall and temperature (20°C), after which the incubates were Wedel, 1986). filtered using a 12-well cell harvester (Titertek, Ska- Therefore, in order to obtain a reliable method for tron, Lier, Norway) and buffer-presoaked glass fiber measuring the dopamine dissociation constant at filter mats (No. 7034, Skatron, Sterling, VA). After D2High and to compare the densities of the various filtering the incubate the filter mat was rinsed with ligands on cloned human D2 receptors, we compared buffer for 15 sec (7.5 ml buffer). The filters were pushed DOPAMINE DISPLACES [3H]DOMPERIDONE 211 out and placed in scintillation minivials (Packard In- struments, Chicago, IL).
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