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[3H]PD 128907, a Putatively Selective Ligand for the D3 Dopamine Receptor, in Rat Brain: a Receptor Binding and Quantitative Autoradiographic Study Gregory N

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[3H]PD 128907, a Putatively Selective Ligand for the D3 Dopamine Receptor, in Rat Brain: a Receptor Binding and Quantitative Autoradiographic Study Gregory N Binding of [3H]PD 128907, a Putatively Selective Ligand for the D3 Dopamine Receptor, in Rat Brain: A Receptor Binding and Quantitative Autoradiographic Study Gregory N. Bancroft, B.S., Kimberly A. Morgan, B.S., Rebecca J. Flietstra, Ph.D., and Beth Levant, Ph.D. [3H]PD 128907 has been proposed as a selective ligand for on the binding of either ligand. These observations indicate the D3 dopamine receptor. This study characterizes the labeling of a dopaminergic site with characteristics binding of this radioligand in rat brain using in vitro consistent with the D3 receptor. In autoradiographic radioligand binding and autoradiographic methods. In studies, highest densities of [3H]PD 128907–labeled sites radioligand binding studies, [3H]PD 128907 exhibited 0.3 were observed in islands of Calleja followed by the nucleus nmol/L affinity for a single, low density site in ventral accumbens, nucleus of the horizontal limb of the diagonal striatal membranes. The pharmacological profile for [3H]PD band, the molecular layer of cerebellar lobule X, and the 128907 was similar to that of [3H](1)-7-OH-DPAT with ventral caudate/putamen. [Neuropsychopharmacology the rank order of potency for dopamine agonists being PD 18:305–316, 1998] © 1998 American College of 128907 ø 7-OH-DPAT ø quinpirole > dopamine; for Neuropsychopharmacology. Published by Elsevier antagonists, spiperone . (1)-butaclamol ø domperidone > Science Inc. haloperidol . SCH 23390. Guanyl nucleotides had no effect 3 3 KEY WORDS: [ H]PD 128907; [ H]7-OH-DPAT; D3 (Bouthenet et al. 1991; Sokoloff et al. 1990). These brain dopamine receptor; Rat brain; Receptor binding; Receptor regions are terminal fields of the mesolimbic dopamine autoradiography projection that is hypothesized to be involved in pro- [3H]PD 128907 has been identified as a putatively selec- ducing psychotic symptoms in schizophrenia (Stevens 1973). Furthermore, unlike mRNA for the D2 receptor, tive ligand for the D3 dopamine receptor (Akunne et al. relatively little D3 mRNA is expressed in the caudate/ 1995). A member of the D2 receptor family, the D3 site is of particular interest because its mRNA is expressed putamen (Bouthenet et al. 1991; Sokoloff et al. 1990). preferentially in brain regions such as the nucleus ac- This suggests that the D3 site may be a target for novel cumbens, olfactory tubercle, and islands of Calleja antipsychotic drugs that might be free of extrapyrami- dal effects. It has also been suggested that the D3 recep- tor may play a role in the reinforcing properties of co- From the Department of Pharmacology (BL), Toxicology, and caine (Caine and Koob 1993) and might thus represent a Therapeutics, University of Kansas Medical Center, Kansas City, Kansas. potential target in the treatment of drug abuse. Address correspondence to: Beth Levant, Ph.D., Department of Since the cloning of the D3 receptor, several radioli- Pharmacology, University of Kansas Medical Center, 3901 Rainbow gands thought to be selective for this site have been syn- Blvd., Kansas City, KS 66160-7417. 3 1 Received March 14, 1997; revised August 14, 1997; accepted thesized including [ H]PD 128907 (R-( )-trans-3,4,4a, August 18, 1997. 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[3,4-b]- NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 4 © 1998 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/98/$19.00 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(97)00162-0 306 G.N. Bancroft et al. NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 4 1,4-oxazin-9-ol]) (Akunne et al. 1995) and [3H]7-OH- dition of membrane homogenate. Nonspecific binding DPAT (7-hydroxy-diphenylaminotetralin) (Lévesque et al. was defined by 10 mmol/L quinpirole. Preliminary ex- 1992). However, there is some controversy over the se- periments indicated the optimal incubation time at 238C 3 lectivity of [ H]7-OH-DPAT for the D3 receptors over to be 3 h. The reaction was terminated by rapid filtration the D2 (Gonzales and Sibley 1995). Interaction of the through Whatman GF/B filters pretreated with 0.5% ligand with the sigma site has also been reported (Wal- polyethyleneimine using a Brandel cell harvester. Fil- lace and Booze 1995). Although confusion over the se- ters were washed 3 times with 3 ml ice-cold buffer (50 lectivity of [3H]7-OH-DPAT may be due to the use of mmol/L Tris; pH 7.4 at 238C), and placed in scintilla- different assay protocols, the conflicting reports have tion vials. After the addition of Beckman Ready limited the utility of this ligand as a tool for the study of Protein1 scintillation cocktail, vials were shaken, al- D3 sites in brain. On the other hand, PD 128907 pro- lowed to equilibrate for 2 h, and radioactivity quanti- duced behavioral and neurochemical effects in brain tated using a Beckman 6500 scintillation counter. Pro- suggestive of activity at the D3 site (Pugsley et al. 1995). tein concentrations were determined using the BCA Likewise, [3H]PD 128907 exhibited significant selectiv- method (Pierce, Rockford, IL). Specific binding of [3H]PD ity in transfected cell lines (Akunne et al. 1995). How- 128907 is expressed as fmol/mg protein. Data from sat- ever, the utility of this ligand in rat brain has not yet uration and competition experiments were analyzed been demonstrated. using the nonlinear least-squares curve-fitting program Because comprehensive study of a novel receptor LIGAND. Results are expressed as the mean 6 SE. system in brain requires the ability to selectively visual- ize the receptor protein, as well as receptor mRNA, the 3 1 3 [ H]( )-7-OH-DPAT Binding Assays utility of [ H]PD 128907 as a D3-selective agent was eval- uated. The pharmacological profile, guanyl nucleotide Assays were performed as described for [3H]PD 128907 regulation, and regional distribution of [3H]PD 128907– (see above) with the following exceptions. Membranes labeled sites in rat brain are described and assessed us- were prepared in assay buffer (50 mmol/L HEPES, 1 ing receptor binding and quantitative autoradiographic mmol/L EDTA; pH 7.4, at 48C) to yield a final concen- methods. tration of 7.5 mg o.w.w./ml. The concentration of [3H] (1)-7-OH-DPAT (139 Ci/mmol; Amersham, Arlington Heights, IL) was z0.2 nmol/L for single point assays. MATERIALS AND METHODS Nonspecific binding was defined by 10 mmol/L quin- pirole. Preliminary experiments indicated the optimal [3H]PD 128907 Binding Assays incubation time at 238C to be 1 h. Bound ligand was The [3H]PD 128907 binding assays were performed ac- separated from free by rapid filtration through un- cording to a modification of the methods of Akunne et treated Whatman GF/B filters. The wash buffer was 50 al. (1995). Discrete brain regions were isolated by free- mmol/L Tris, 120 mmol/L NaCl; pH 7.4 at 238C. hand dissection on ice from the brains of adult male Sprague-Dawley rats (Harlan Bioproducts, Indianapolis, Receptor Autoradiography with [3H]PD 128907 IN). Brain tissue was homogenized with a PRO250 Ho- mogenizer (setting 4 of 6) for 10 s in 20 volumes of as- Adult male Sprague-Dawley (200–300 g; Charles River say buffer (50 mmol/L Tris, 1 mmol/L EDTA; pH 7.4). Laboratories, Wilmington, DE) were killed by decapita- The crude homogenate was centrifuged twice at 48,000 3 tion, brains rapidly removed, frozen in isopentane, and g for 15 min, resuspending the pellet in 20 volumes of as- stored at 2708C until sectioning. Sagittal and coronal say buffer each time. The final pellet from membrane brain sections (20 mm) were cut on a cryostat, thaw- preparation was resuspended in buffer to yield a final mounted onto chrome-alum/gelatin-coated slides and concentration of 10 mg original wet weight (o.w.w.)/ stored at 2708C until use. ml. Binding assays were performed in duplicate in dis- [3H]PD 128907 autoradiography was performed ac- posable polystyrene tubes. The final assay volume was cording to a modification of methods previously de- 0.5 ml. For binding site saturation studies, 8–10 concen- scribed (Levant et al. 1993). Optimal assay conditions trations of (1)-[N-propyl-2,3-3H]PD 128907 (116 Ci/ were determined in preliminary wash-out and associa- mmol; Amersham, Arlington Heights, IL) were used. tion experiments. Slide-mounted brain sections were For all other studies, the final concentration of [3H]PD brought to room temperature and allowed to dry thor- 128907 was z0.3 nmol/L. Unless otherwise noted, ven- oughly. Duplicate sections from the same animal were tral striatal (nucleus accumbens and olfactory tubercle) used for each data point. Slides were incubated with membranes were incubated with [3H]PD 128907 and z0.7 nmol/L [3H]PD 128907 in assay buffer (50 mmol/ various concentrations of competing drugs (RBI, Nat- L Tris, 1 mmol/L EDTA, pH 7.4 at 238C) for 2 h at 238C. ick, MA) or 59-guanylyl-imidodiphosphate (Gpp(NH)p) Nonspecific binding was defined in the presence of 1 (Sigma, St. Louis, MO). Binding was initiated by the ad- mmol/L spiperone. After incubation, slides were dipped NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 4 [3H]PD 128907 Binding in Brain 307 in ice-cold assay buffer, washed for two consecutive and length of incubation (data not shown). When used z 2-min periods in ice-cold assay buffer, dipped in ice- at a concentration equal to the KD value ( 0.3 nmol/L), 3 cold deionized H2O, and dried under a cool air stream. [ H]PD 128907 binding reached steady state within 3 h Radiolabeled sections were subsequently apposed to at 238C. At a final tissue concentration of 10 mg o.w.w./ 3H-Hyperfilm (Amersham, Arlington Heights, IL) with ml, less than 3% of the total [3H]PD 128907 was bound 20 mm [3H]methylmethacrylate autoradiographic stan- at steady state.
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