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Norepinephrine Neuronal Uptake Binding Sites in Rat Brain

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Norepinephrine Neuronal Uptake Binding Sites in Rat Brain Proc. Natl Acad. Sci. USA Vol. 78, No. 8, pp. 5250-5254, August 1981 Neurobiology Norepinephrine neuronal uptake binding sites in rat brain membranes labeled with [3Hldesipramine (imipramine/tricyclic antidepressants/serotonin/sodium and neurotransmitter transport) CHI-MING LEE AND SOLOMON H. SNYDER* Departments of Neuroscience, Pharmacology and Experimental Tlerapeutics, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 725 Nort Wolfe Street, Baltimore, Maryland 21205 Contributed by Solomon H. Snyder, May 7, 1981 ABSTRACT Neuronal uptake recognition sites in norepineph- MATERIALS AND METHODS rine neurons have been labeled with the antidepressant [3H]de- sipramine. A high-affinity component of[3H]desipramine binding DMI was from Merrell-National Laboratory (Cincinnati, OH), to rat cerebral cortex membranes is abolished selectively by 6- imipramine was from Geigy Pharmaceuticals (Ardsley, NY), hydroxydopamine lesions, which destroy central catecholamine and chlorprom- neurons. The high-affinity [3H]desipramine binding has a nano- (+)- and (-)-amphetamine, chlorpheniramine, molar affinity constant fordesipramine and is inhibited by tricyclic azine were generous gifts from Smith, Kline and French Lab- antidepressants with potencies that correlate with their ability to oratories, mianserin was from Organon, benztropine, cypro- inhibit the neuronal uptake of norepinephrine. [3H]Desipramine heptidine, and amitriptyline were from Merck Sharp and binding to the uptake sites is markedly stimulated by sodium, with Dohme, (+)-epinephrine and phenylephrine were from Ster- potassium, lithium, and choline being much less effective. The ling-Winthrop Research Institute (Rensselaer, NY), chlorimi- ability to monitor norepinephrine neuronal uptake "receptors" in pramine was from CIBA Pharmaceutical, iprindole was from simple binding studies should permit adifferential analysis ofdrug Wyeth, clonidine was from Boehringer Ingelheim (Elmsford, influences on the norepinephrine recognition site and the trans- NY), prazosin and doxepin were from Pfizer, 6-hydroxydopa- location mechanism. The regulation of [3H]desipramine binding mine (6-OH-dopamine) and NE were from Sigma. by sodium may help clarify how sodium influences neurotrans- (+)_[3H]NE (7.5 Ci/mmol), [3H]DMI (57.0 Ci/mmol), and mitter uptake. [3H]imipramine (74.3 Ci/mmol) were obtained from New En- gland Nuclear (1 Ci = 3.7 x 1010 becquerels). After its synaptic release the neurotransmitter norepinephrine For [3H]DMI binding, male Sprague-Dawley rats weighing (NE) is reaccumulated into nerve terminals by a specific uptake 150-200 g were killed by decapitation and each cerebral cortex system, which serves to terminate its synaptic actions (1-3). The was homogenized in 30 vol of ice-cold assay buffer (50 mM tricyclic antidepressants are potent inhibitors of the neuronal Tris.HC1/120 mM NaCV5 mM KCl, pH 7.4) with a Brinkmann uptake ofboth NE and serotonin, effects which are thought to Polytron PT-10 at a setting of5 for 10 sec. The homogenate was explain their clinical antidepressant actions (4). Among the tri- centrifuged at 50,000 x g for 10 min. The pellet was resus- cyclic antidepressants, the tertiary amine forms tend to be rel- pended in 30 vol of the assay buffer by a Polytron at setting 5 atively more potent competitive inhibitors of serotonin than of for 5 sec and centrifuged again. This washing procedure was NE uptake, whereas the reverse holds true for secondary amine repeated twice and the final pellet was resuspended in 30 vol antidepressants such as desipramine (DMI) (5, 6). of assay buffer. Molecular studies of biogenic amine neuronal uptake in the The binding of[3H]DMI was routinely measured in triplicate brain have usually involved measurements ofthe accumulation at 0°C for 1 hr, using 200 ,ul ofthe membrane preparation with ofradiolabeled amines by slices or pinched-offnerve terminals, 0.2-10 nM [3H]DMI in the presence or absence of various called "synaptosomes" (3, 5). The NE uptake recognition bind- tested drugs in a final volume of 250 pl. At the end of the in- ing site on NE nerve terminals has not been studied biochem- cubation period, 5 ml ofice-cold assay buffer was added to each ically separately from the Na+,K+-ATPase-dependent amine tube and its content was filtered immediately under reduced accumulating system. For neurotransmitter postsynaptic re- pressure through Millipore glass fiber filters. Each ofthe filters ceptors, recognition sites can be labeled by the direct binding was then washed three times with 5 ml of ice-cold buffer and ofradioactive forms of the transmitter or related drugs (7). Re- radioactivity was measured by liquid scintillation spectrometry, cently, [3H]imipramine binding to brain (8) and platelet (9) using Formula 947 scintillation mixture (New England Nu- membranes has been described; the binding properties suggest clear). Nonspecific binding, unless otherwise stated, was de- that the binding sites represent serotonin neuronal uptake fined as binding in the presence of 100 AM DMI. Specific bind- recognition sites. Relative drug potencies in competing for ing of [3H]DMI was calculated by subtracting the nonspecific [3H]imipramine binding parallel affinities for the serotonin up- from total binding and expressed as fmol/mg of protein. take system, and selective destruction of serotonin neuronal To study the effect of various monovalent cations on systems reduces [3]imipramine binding (10-12). [3H]DMI binding, rat cortical membranes were prepared in 50 We now report a high-affinity binding of [3H]DMI to rat mM Tris HCl buffer (pH 7.4). Specific binding was measured brain membranes that appears to label recognition sites for the at 2 nM [3H]DMI in the presence of various concentrations of neuronal uptake of NE. sodium, potassium, lithium, or choline chloride. The publication costs ofthis article were defrayed in part by page charge Abbreviations: DMI, desipramine; NE, norepinephrine; 6-OH-dopa- payment. This article must therefore be hereby marked "advertise- mine, 6-hydroxydopamine. ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. * To whom reprint requests should be addressed. 5250 Downloaded by guest on September 24, 2021 Neurobiology: Lee and Snyder Proc. Nad Acad. Sci. USA 78 (1981) .5251 For 6-OH-dopamine injections, male adult Sprague-Dawley 700 NaCl rats weighing 150-200 g were anesthetized with Equithesin. 6-OH-dopamine (200 1Lg/201) -was dissolved in 0.9% NaCl containing 1% ascorbic. acid and delivered into the left lateral I 600 ventricle over a period of2 min under stereotaxic control (13). Cm For some animals, a second dose of 6-OH-dopamine (200 ,ug/ O -500 0 20 Aul) was given 24 hr later. Sham-operated animals received bO the same volume of vehicle. Animals were decapitated 3 or 7 ..400c .0 days after the second injection and each cerebral cortex was c.> homogenized in 10 vol of ice-cold 0.3 M sucrose. The homog- * 300 enate was centrifuged at 50,000 X g for 10 min, the pellet was C010 100 resuspended in 10 vol of0.3 M sucrose, and.aliquots were saved -- for [3HINE uptake studies. The rest of the homogenate was °E 200 diluted with the:binding assay buffer, homogenized with,a Poly- .KCI tron, and centrifuged at 50,000 x gfor 10 min. The membranes C-0 100 .00o- o were washed twice with 30 vol ofthe assay buffer, and-the final pellet was resuspended in 30 vol of-the assay buffer by Polytron ZR treatment. Binding of [3H]DMI was performed as described in 100 200 300 the.previous section, using 2 nM [3H]DMI. Salt, mM FIG. 1. Sodium dependency of [3HIDMI bindingto rat cerebral cor- RESULTS tical membranes. Specific binding of [3H]DhMI was measured at 2 nM General Properties of[3H]DMIBinding. Initial experiments [3H]DMI in the presence of various concentrations of sodium (e) or at 370C showed little difference between total binding of potassium (o) chloride. Specific binding of [3H]DMI in the absence of sodium was 19.2 ± 2.7 fmol/mg of protein (mean ± SEM). Results are [3H]DMI and nonspecific binding measured with either -10 expressed as percent of binding relative to that of the no-sodium con- AM or 100 AM unlabeled DMI. However, at 0C reproducible trol and are the means of three experiments. specific binding could be obtained with several regions of rat brain. With washed rat cerebral cortical membranes incubated- with 2 nM [3H]DMI, total binding was about 3200 cpm and [3H]DMI binding. When membranes were prepared after.ini- nonspecific binding in the presence of.100 pM DMI or 10 tial homogenization in sucrose under conditions to produce syn- AM DMI, respectively, was 900 and 1200 cpm. Under standard aptosomes, nonspecific binding measured with 100 AM DMI binding conditions radioactivity in the medium represented was about 40% of total binding. In the sucrose-prepared mem- unmetabolized [3H]DMI when assayed by silica gel thin-layer branes, nonspecific binding measured with 10 A.tM DMI was chromatography (ethanol/ammonium hydroxide, 29:1, vol/ 65-70% of total binding, whereas with membranes homoge- vol). nized with a Polytron in Tris buffer, nonspecific binding with Regional dissection experiments indicated that most brain 10 pM DMI was about 35% of-total binding. Because the total regions displayed substantial levels ofspecific [3H]DMI-binding except for the corpus striatum and cerebellum, areas with low- est endogenous NE content, .whose levels were substantially 100 less than those of the cerebral cortex. z 80 The .[3H]DMI binding site appears to be labile. Storing '° 60 washed membranes overnight at -20'C produced a.20-30% CO-, loss ofspecific [3H]DMI binding. Preincubation ofmembranes 0 at 37C for 1.hr followed by binding assays at 0C -resulted.in 0 40 a 40% decrease.in binding. 20 Cation Dependence.of Specific [3H]DMI Binding. The NE neuronal uptake system is absolutely dependent upon sodium g 0 (2).
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