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Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey

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Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey The Journal of Neuroscience, August 1, 2001, 21(15):5594–5500 Vulnerability of 125I-␣-Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey Maryka Quik,1 Yelena Polonskaya,1 Jennifer M. Kulak,1 and J. Michael McIntosh2 1The Parkinson’s Institute, Sunnyvale, California 94089, and 2Department of Biology and Psychiatry, University of Utah, Salt Lake City, Utah 84112 Parkinson’s disease, a neurodegenerative movement disorder age to the nigrostriatal system and parkinsonism. Autoradio- characterized by selective degeneration of nigrostriatal dopa- graphic analysis showed that 125I-␣-CtxMII sites were selec- minergic neurons, affects ϳ1% of the population over 50. Be- tively reduced (Ն99%) in the basal ganglia and that the lesion- cause nicotinic acetylcholine receptors (nAChRs) may repre- induced decreases correlated well with declines in the sent an important therapeutic target for this disorder, we dopamine transporter, a marker of dopaminergic neuron integ- performed experiments to elucidate the subtypes altered with rity. These findings may indicate that most or all of 125I-␣- nigrostriatal damage in parkinsonian monkeys. For this purpose CtxMII-labeled nAChR subtypes in the basal ganglia are we used 125I-␣-conotoxin MII (CtxMII), a relatively new ligand present on nigrostriatal dopaminergic neurons, in contrast to that identifies ␣3 and/or ␣6 subunits containing nAChR sub- 125I-epibatidine sites. These data suggest that the development types. In brain from untreated monkeys, there was saturable of ligands directed to nAChR subtypes containing ␣3 and/or ␣6 125I-␣-CtxMII binding to a single population of high-affinity subunits may yield a novel treatment strategy for parkinsonian ϭ nicotinic sites (Kd 0.9 nM), primarily localized in the visual, patients with nigrostriatal dopaminergic degeneration. habenula-interpeduncular, and nigrostriatal–mesolimbic path- Key words: ␣-conotoxin MII; ␣3 nAChRs; ␣6 nAChRs; MPTP; ways. Administration of the selective dopaminergic neurotoxin monkeys; autoradiography; nigrostriatal system; dopamine; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine resulted in dam- Parkinson’s disease Accumulating evidence indicates that neuronal nicotine acetyl- disease (Morens et al., 1995; Balfour and Fagerstrom, 1996; choline receptors (nAChRs) may be important in Parkinson’s Gorell et al., 1999), with the risk of developing Parkinson’s disease, a movement disorder characterized by degeneration of disease reduced from 20 to 80% in tobacco users. the nigrostriatal dopaminergic system (Balfour and Fagerstrom, Studies to investigate the nAChR subtypes that mediate the 1996; Quik and Jeyarasasingam, 2000). Nicotinic receptors are effects of nicotine are important because these receptors repre- present in the basal ganglia (Marks and Collins, 1982; Schwartz et sent potential targets for Parkinson’s disease therapy to amelio- al., 1982, 1984; Clarke et al., 1985; Perry et al., 1987, 1995; Aubert rate motor symptoms and/or protect against neurodegeneration. et al., 1992; Marks et al., 1992, 1996; Gotti et al., 1997; Court et nAChRs form a large family of ligand-gated cation channels with al. 2000), and nAChR stimulation evokes striatal dopamine (DA) diverse structures and properties (Changeux et al., 1998; Jones et release (Grady et al., 1992; Marshall et al., 1997; Wonnacott, al., 1999; Lukas et al., 1999; Picciotto et al., 2000). Subunit 1997). Moreover, nicotine and nAChR ligands modulate motor mRNAs present in basal ganglia include ␣2to␣7 and ␤2to␤4 control in rodents, monkeys, and humans (Ishikawa and (Gotti et al., 1997; Wonnacott, 1997; Quik et al., 2000a,b). There Miyatake, 1993; Fagerstrom et al., 1994; Schneider et al., 1998; is thus the potential for receptors with multiple subunit combi- Domino et al., 1999; Kelton et al., 2000), possibly through acti- nations. However, our knowledge of the subtypes expressed in the ␣ ␣ vation of 4 and/or 6 containing nAChRs (Sorenson et al., 1998; basal ganglia has been limited in part by the small number of Arroyo-Jiminez et al., 1999; Le Novere et al., 1999; Ross et al., subtype-selective nAChR radioligands. The use of tritiated nico- 2000). tine and cytisine provides some selectivity for ␣4- and ␤2- Not only does nicotinic receptor stimulation modulate locomo- containing receptors, whereas 125I-␣-bungarotoxin and 3H- tor activity, but nicotine has also been reported to exert a neu- methyllycaconitine selectively bind ␣7-containing receptors roprotective role against dopaminergic damage both in culture (Gotti et al., 1997; Lukas et al., 1999; Whiteaker et al., 1999). and in vivo (Janson et al., 1988; Carr and Rowell, 1990; Belluardo However, radiolabeled epibatidine is relatively nonselective for et al., 1998; Maggio et al., 1998; Quik and Jeyarasasingam, 2000). different nicotinic receptor subtypes and may bind to receptors Moreover, over 50 epidemiological studies indicate that there is containing ␣2 through ␣6 subunits (Perry et al., 1995; Davila- an inverse relationship between tobacco use and Parkinson’s Garcia et al., 1997). 125I-␣-conotoxin MII (CtxMII) is a relatively new ligand that Received Feb. 6, 2001; revised April 30, 2001; accepted May 8, 2001. appears to be selective for receptors containing ␣3 and/or ␣6 This work was supported by the California Tobacco Related Disease Research Program Grant TRDRP 7RT-015 (M.Q.), National Institute on Drug Abuse Grant subunits (Cartier et al., 1996; Kulak et al., 1997; Luo et al., 1998; DA12242 (J.M.M.), National Institute of Mental Health Grant MH53631 (J.M.M.), McIntosh et al., 1999; Vailati et al., 1999; Kuryatov et al., 2000; and National Institute of General Medical Sciences Grant GM48677 (J.M.M.). Whiteaker et al., 2000a). Because this represents a valuable new Correspondence should be addressed to Dr. Maryka Quik, The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, CA 94089. E-mail: [email protected]. tool to define a subset of nicotinic receptors, we initiated exper- Copyright © 2001 Society for Neuroscience 0270-6474/01/215494-07$15.00/0 iments with 125I-␣-CtxMII in normal and 1-methyl-4-phenyl- Quik et al. • 125I-␣-CtxMII Sites after Nigrostriatal Damage J. Neurosci., August 1, 2001, 21(15):5594–5500 5495 1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkey brain. [125I]RTI-121 autoradiography. 3␤-(4-[ 125I]iodophenyl)tropane-2␤- 125 Monkeys were selected for study because the neuroanatomical carboxylic acid isopropyl ester ([ I]RTI-121; 2200 Ci/mmol; NEN, Boston, MA) was used to identify DA transporters (Quik et al., 2000c). organization of both the basal ganglia and the nAChR subunit Thawed sections were preincubated in buffer containing (in mM): 50 mRNA distribution closely resemble that of humans. Moreover, Tris-HCl, pH 7.4, 120 NaCl, and 5 KCl two times for 15 min at RT. This monkeys treated with the neurotoxin MPTP exhibit behavioral, was followed bya2hrincubation in the same buffer, also containing 125 pathological, and neurochemical changes similar to those ob- 0.025% BSA, 1 ␮M fluoxetine, and 50 pM [ I]RTI-121. The sections served in Parkinson’s disease (Langston et al., 2000; Quik et al., were washed four times for 15 min at 4°C in preincubation buffer, dipped in ice-cold water, air-dried, and placed against Hyperfilm ␤-film for 1–3 2000a,b,c). d with 125I-microscale standards. The uptake inhibitor nomifensine (100 ␮M) was used to define nonspecific binding. There was no binding of the MATERIALS AND METHODS radiolabel to the tissue sections in the presence of nomifensin, with blank binding being identical to the film background. Animals. Twenty young adult male and female squirrel monkeys (Saimiri Quantitation and data analysis. The squirrel monkey (Saimiri sciureus) sciureus) weighing from 0.595 to 0.752 kg were obtained from Osage atlas of Emmers and Akert (1963) was used for identification of the Research Primates (Osage Beach, MO). All animals were housed in a different brain regions. Nissl-stained sections were used to identify brain 13/11 hr light/dark cycle with ad libitum access to food and water. After areas. The area delineating the appropriate regions was quantitated using quarantine and testing according to standard veterinary practice, the computer-assisted densitometry (ImageQuant; Molecular Dynamics, animals were randomly assigned to the control or MPTP treatment Sunnyvale, CA) under standardized light and power conditions. Optical groups. All procedures used in this study conform to the National densities of the film images were determined by subtracting background Institutes of Health (NIH) Guide for the Care and Use of Laboratory from tissue values. The optical density values were converted to femto- Animals and were approved by the Institutional Animal Care and Use moles per milligram of tissue by interpolation from standard curves that Committee. were generated from 125I standards exposed with the tissue sections. The Behavioral testing and MPTP treatment. Quantitative activity assess- sample optical density readings for both the receptor and transporter ment was performed using a computerized movement monitor cage data were within the dynamic (linear) range of the film. The saturation containing an array of infrared sensors (Quik et al., 2000b). After an and competition data represent the results of three or four experiments, initial acclimatization period, the locomotor activity of the monkeys was using one or two tissue sections per experiment for each concentration of monitored fora1hrperiodfor8–12consecutive days, at the same time radiolabeled 125I-␣-CtxMII (saturation) or competing ligand. In all other daily. Then, the animals were assigned randomly to treatment with experiments, the value for the receptor binding for any brain region per MPTP (2 mg/kg, s.c.) or saline. Two to 3 weeks later, locomotor activity monkey was obtained by taking the average value from two to four was measured again as described above, and animals were rated by two independent experiments, with one or two consecutive tissue sections raters, one of whom was blinded, for motor deficits using a parkinsonian used in each experiment. All values are expressed as the mean Ϯ SEM rating scale for nonhuman primates (Langston et al., 2000). The disabil- of the indicated number of animals.
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