European Journal of Pharmacology: Molecular Pharmacology最新文献

{"title":"Physostigmine, galanthamine and codeine act as ‘noncompetitive nicotinic receptor agonists’ on clonal rat pheochromocytoma cells","authors":"Alexander Storch ,&nbsp;André Schrattenholz ,&nbsp;Julia C. Cooper ,&nbsp;El Moeiz Abdel Ghani ,&nbsp;Oliver Gutbrod ,&nbsp;Karl-Heinz Weber ,&nbsp;Sigrid Reinhardt ,&nbsp;Christina Lobron ,&nbsp;Bernhard Hermsen ,&nbsp;Vukiç Šoškiç ,&nbsp;Edna F.R. Pereira ,&nbsp;Edson X. Albuquerque ,&nbsp;Christoph Methfessel ,&nbsp;Alfred Maelicke","doi":"10.1016/0922-4106(95)00080-1","DOIUrl":"10.1016/0922-4106(95)00080-1","url":null,"abstract":"<div><p>The acetylcholine esterase inhibitor (−)-physostigmine has been shown to act as agonist on nicotinic acetylcholine receptors from muscle and brain, by binding to sites on the α-polypeptide that are distinct from those for the natural transmitter acetylcholine (Schröder et al., 1994). In the present report we show that (−)-physostigmine, galanthamine, and the morphine derivative codeine activate single-channel currents in outside-out patches excised from clonal rat pheochromocytoma (PC12) cells. Although several lines of evidence demonstrate that the three alkaloids act on the same channels as acetylcholine, the competitive nicotinic antagonist methyllycaconitine only inhibited channel activation by acetylcholine by not by (−)-physostigmine, galanthamine or coedeine. In contrast, the monoclonal antibody FK1, which competitively inhibits (−)-physostigmine binding to nicotinic acetylcholine receptors, did not affect channel activation by acetylcholine but inhibited activation by (−)-physostigmine, galanthamine and codeine. The three alkaloids therefore act via binding sites distinct from those for acetylcholine, in a ‘noncompetitive’ fashion. The potency of (−)-physostigmine and related compounds to act as a noncompetitive agonist is unrelated to the level of acetylcholine esterase inhibition induced by these drugs. (−)-Physostigmine, galanthamine and codeine do not evoke sizable whole-cell currents, which is due to the combined effects of low open-channel probability, slow onset and slow inactivation of response. In contrast, they sensitize PC12 cell nicotinic receptors in their submaximal response to acetylcholine. While the abundance of nicotinic acetylcholine receptor isoforms expressed in PC12 cells excludes identification of specific nicotinic acetylcholine receptor subtypes that interact with noncompetitive agonists, the identical patterns of single-channel current amplitudes observed with acetylcholine and with noncompetitive agonists suggested that all PC12 cell nicotinic acetylcholine receptor subtypes that respond to acetylcholine also respond to noncompetitive agonist. The action of noncompetitive agonists therefore seems to be highly conserved between nicotinic acetylcholine receptor subtypes, in agreement with the high level of structural conservation in the sequence region harboring major elements of this site.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 3","pages":"Pages 207-219"},"PeriodicalIF":0.0,"publicationDate":"1995-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)00080-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18594736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Staurosporine inhibits inositol phosphate formation in bovine adrenal medullary cells","authors":"Stephen J. Bunn,&nbsp;Heather I. Saunders","doi":"10.1016/0922-4106(95)00082-8","DOIUrl":"10.1016/0922-4106(95)00082-8","url":null,"abstract":"<div><p>The effect of protein kinase C activators and inhibitors on histamine-stimulated phospholipase C in bovine adrenal medullary cells has been investigated. The protein kinase C activators, phorbol 12,13-dibutyrate (PDB) or <em>sn</em>-1,2-dioctanoylglycerol (DOG), inhibited histamine-stimulation of phospholipase C. This inhibition was prevented by the protein kinase C-selective inhibitor Ro 31-8220 (3-{(1-[3-(2-isothioureido) propyl]indol-3-y(-4-(1-methylindol-3-yl)-3-pyrrolin-2,5-dione) but not the broad spectrum protein kinase inhibitor staurosporine. Indeed staurosporine on its own inhibited both the histamine-stimulated response and, in permeabilized cells, phospholipase C activated by Ca²⁺. Staurosporine inhibition of phospholipase C is unlikely to be mediated via protein kinase A or Ca²⁺/calmodulin-dependent protein kinase because it was not reproduced by selective inhibition of these kinases. Starausporine treatment, however, reduced inositol phospholipid levels in stimulated cells. Thus staurosporine and Ro 31-8220, two widely used protein kinase C inhibitors, have quite different effects on phospholipase C activation. Furthermore, staurosporine may cause this inhibition through a reduction in the level of phospholipase C substrate.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 3","pages":"Pages 227-236"},"PeriodicalIF":0.0,"publicationDate":"1995-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)00082-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18594738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional effects of the 5-HT1D receptor antagonist GR 127,935 at human 5-HT1Dα, 5-HT1Dβ, 5-HT1A and opposum 5-HT1B receptors","authors":"Petrus J. Pauwels,&nbsp;Christiane Palmier","doi":"10.1016/0922-4106(95)90021-7","DOIUrl":"https://doi.org/10.1016/0922-4106(95)90021-7","url":null,"abstract":"<div><p>The functional activity and selectivity of the novel 5-HT_1D receptor antagonist GR 127,935 (2′-methyl-4′-(5-methyl-1,2,4 oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide) was investigated at cloned human 5-HT_1A, 5-HT_1Dα HT_1Dβ and opposum kidney (OK) 5-HT_1B receptor sites. 5-HT₁ receptor-mediated activity was studied by measuring the inhibition of forskolin-induced cAMP formation in cell lines expressing these receptors (<em>B</em>_max (fmol/mg protein): human epitheloid carcinoma HeLa/5-HT_1A: 1285, OK/5-HT_1B: 52, Chinese hamster ovary CHO-K1/5-HT_1Dα: 181 and CHO-K1/5-HT_1Dβ: 685). GR 127,935 did not show 5-HT_1Dβ receptor-mediated agonist activity in permanently transfected CHO-K1 cells, whereas at submicromolar and higher concentrations intrinsic agonist activity was observed in HeLa/5-HT_1A,OK/5-HT_1B and CHO-K1/5-HT_1Dα cells. GR 127,935 showed potent (<em>K</em>_B value: 1.3 nM) and silent antagonism at CHO-K1/5-HT_1Dβ receptor sites. The antagonists activtity of 1 μM of GR 127,935 at CHO-K1/5-HT_1Dα and OK/5-HT_1B receptor sites was only partial and less pronounced. This contrasts with the silent antagonism of methiothepin at the 5-HT_1Dα (<em>K</em>_B value = 11.8 nM), 5-HT_1Dβ (<em>K</em>_B value = 6.9 nM) and 5-HT_1B (<em>K</em>_B value = 49.3 nM) receptor subtypes. GR 127,935, when tested at 10 μM, was found to be a weak and partial antagonist of HeLa/5-HT_1A receptors. In conclusion, GR 127,935 is a potent and effective antagonist of cloned human 5-HT_1Dβ receptor sites in transfected CHO-K1 cells but is only able to partially antagonise CHO-K1/5-HT_1Dα, OK/5-HT_1B and Hela/5-HT_1A receptor sites at micromolar concentrations.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 95-103"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90021-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterisation of inositol 1,4,5-trisphosphate binding sites in rabbit aortic smooth muscle","authors":"Timothy V. Murphy ,&nbsp;Lisa M. Broad,&nbsp;Christopher J. Garland","doi":"10.1016/0922-4106(95)90027-6","DOIUrl":"10.1016/0922-4106(95)90027-6","url":null,"abstract":"<div><p>The present study investigated the characteristics of <span>D</span>-<em>myo</em>-inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) binding sites in crude membrane preparations of rabbit aortic smooth muscle. A particular aim was to demonstrate if increases in cytoplasmic cyclic guanosine 3′:5′ monophosphate (cGMP), which mediates the effect of nitrovasodilators, may cause smooth muscle relaxation in part by the displacement of Ins(1,4,5)P₃ binding. Negligible Ins(1,4,5)P₃ binding was observed at pH &lt; 7, while maximum binding occurred over the pH range 8–9. Saturation analysis of isotopic dilution binding data revealed an apparently homogenous population of Ins(1,4,5)P₃ binding sites with a <em>K</em>_D of 4.02 ± 0.53 nM and a <em>B</em>_max of 27.7 ± 4.6 fmol/mg protein. Heparin, an Ins(1,4,5)P₃ receptor antagonist, inhibited binding with an IC₅₀ of 11.43 ± 2.81 <em>ω</em>g/ml. The ability of other polyphosphate compounds to inhibit Ins(1,4,5)P₃ binding in this preparation was also examined. <span>D</span>-<em>myo</em>-Inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P₄), adenosine 5′-triphosphate (ATP) and guanosine 5′-triphosphate (GTP) inhibited Ins(1,4,5)P₃ binding, although each was significantly less potent that Ins(1,4,5)P₃. In contrast, cyclic guanosine 3′:5′ monophosphate (cGMP) did not significantly alter Ins(1,4,5)P₃ binding in rabbit aortic smooth muscle. This observation suggests that competitive inhibition of Ins(1,4,5)P₃ receptor binding is not an important consideration in cGMP-mediate vascular smooth muscle cell relaxation.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 145-150"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90027-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19555740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rolipram inhibition of phosphodiesterase-4 activation","authors":"Michael E. DiSanto,&nbsp;Richard J. Heaslip","doi":"10.1016/0922-4106(95)90031-4","DOIUrl":"10.1016/0922-4106(95)90031-4","url":null,"abstract":"<div><p>Rolipram inhibited U937 cell phosphodiesterase-4 in either the presence or absence of saturating (100 μg/ml) phosphatidic acid in an apparently phospholipid-independent manner, exhibiting similar kinetics (<em>K</em>_i values = 0.41 and 0.59 <em>μ</em>M, respectively). At low concentrations (10 and 100 nM), however, rolipram caused a rightward shift of the phosphatidic acid concentration-response curve for phosphodiesterase-4 activation, suppressing activation by up to 70%. Maximum inhibition of phosphodiesterase-4 activation occurred at phosphatidic acid concentrations of 5–40 μg/ml. The results suggest that rolipram is capable of inhibiting phosphodiesterase-4 by both phospholipid-dependent and phospholipid-independent mechanisms.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 169-172"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90031-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19555744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two human α2-adrenoceptor subtypes α2A-C10 and α2B-C2 expressed in Sf9 cells couple to transduction pathway resulting in opposite effects on cAMP production","authors":"Christian C. Jansson ,&nbsp;Matti Karp ,&nbsp;Christian Oker-Blom ,&nbsp;Johnny Näsman ,&nbsp;Juha-Matti Savola ,&nbsp;Karl E.O. Åkerman","doi":"10.1016/0922-4106(95)90019-5","DOIUrl":"https://doi.org/10.1016/0922-4106(95)90019-5","url":null,"abstract":"<div><p>The baculovirus expression vector system utilizing the strong polyhedrin gene promoter of the <em>Autographa californica</em> nuclear polyhedrosis virus (<em>Ac</em>NPV) was used for high level expression of the two α₂-adrenoceptor subtypes <em>α</em>₂A-C10 and <em>α</em>₂B-C2 in <em>Spodoptera frugiperda</em> (<em>Sf</em>-9) insect cells. For rapid screening of recombinant viruses the luciferase gene was expressed under the early ETL-promoter (early transcript large) in the same plasmid. Both receptor subtypes showed the same rank order of binding affinity for four agonists tested: dexmedetomidine &gt; l-medetomidine = clonidine &gt; noradrenaline. For the <em>α</em>₂A-C10 subtype, these agonists inhibited forskolin stimulated cAMP production through pertussis toxin sensitive G-proteins. In contrast, for the <em>α</em>₂B-C2 subtype the agonists stimulated both basal and forskolin stimulated cAMP production.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 75-83"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90019-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of AMPA/kainate receptors by cyclothiazide increases cytoplasmic free Ca2+ and 45Ca2+ uptake in brain neurons","authors":"Gvido Cebers ,&nbsp;Sture Liljequist","doi":"10.1016/0922-4106(95)90022-5","DOIUrl":"10.1016/0922-4106(95)90022-5","url":null,"abstract":"<div><p>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced Ca²⁺ responses, and their modulation by cyclothiazide, were investigated in two functional assays of Ca²⁺ channel activity. AMPA produced a marked increase in cytoplasmic free Ca²⁺ levels ([Ca²⁺]_i) in single cortical neurons, whereas no such effects of AMPA could be observed in intact cerebellar granule neurons. In monolayer cultures of cortical cells, cyclothiazide caused a pronounced enhancement of AMPA-induced stimulation of ⁴⁵Ca²⁺ uptake, whereas similar studies in cerebellar granule neurons revealed only a weak potentiation of AMPA-induced ⁴⁵Ca²⁺ uptake. Higher concentrations of cyclothiazide alone produced [Ca²⁺]_i oscillations as well as an increase of basal ⁴⁵Ca²⁺ uptake in cortical neurons, whereas no such effects were obtained in cerebellar granule neurons. Our data indicate that AMPA receptors located on cortical and cerebellar granule neurons, respectively, may differ in their permeability to Ca²⁺ and that this difference is markedly potentiated following the application of cyclothiazide.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 105-115"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90022-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19555809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specific accumulation of inositol 1,4,5-trisphosphate in rabbit basilar artery in response to noradrenaline but not 5-hydroxytryptamine","authors":"Timothy V. Murphy ,&nbsp;Christopher J. Garland","doi":"10.1016/0922-4106(95)90026-8","DOIUrl":"10.1016/0922-4106(95)90026-8","url":null,"abstract":"<div><p>This study examined the ability of 5-hydroxytryptamine and noradrenaline to stimulate inositol 1,4,5-trisphosphate (IP₃) mass accumulation in segments of the rabbit basilar artery. 5-Hydroxytryptamine (5-HT, 100 ωM) failed to stimulate any significant accumulation of IP₃ during the 5 min period following its application. In the presence of prazosin, 5-HT (300 ωM) caused a rapid, transient decrease in IP₃ accumulation which was significant after 5 s but had increased to pre-stimulation levels within 15 s. In contrast, noradrenaline (10 ωM) stimulated a rapid, transient accumulation of IP₃ which was significant after 5 s but had declined to basal levels after 60 s. In basilar artery segments bathed in Krebs solution containing 25.7 mM K⁺ (normal concentration 5.7 mM), the basal IP₃ concentration was significantly elevated. The IP₃ accumulation stimulated by either 5-HT or raised K⁺ was not reduced by the presence of the α₁-adrenoceptor antagonist, prazosin (0.1 ωM). In the presence of raised K⁺, 5-hydroxytryptamine caused a rapid, transient inhibition of the K⁺-induced IP₃ accumulation, which was maximal after 5 s but had increased to pre-stimulation levels within 30 s in the continued presence of 5-hydroxytryptamine. Noradrenaline did not affect the IP₃ accumulation induced by raised extracellular [K⁺]. These results provide further evidence that IP₃ is not involved in 5-hydroxytryptamine-induced smooth muscle contraction in the rabbit basilar artery, but support a role for this second messenger in the contraction induced in response to noradrenaline.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 141-144"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90026-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19555813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular pharmacology of LR-B/081, a new non-peptide angiotensin AT1 receptor antagonist","authors":"Anna R. Renzetti ,&nbsp;Marco Criscuoli ,&nbsp;Aldo Salimbeni ,&nbsp;Alessandro Subissi","doi":"10.1016/0922-4106(95)90028-4","DOIUrl":"10.1016/0922-4106(95)90028-4","url":null,"abstract":"<div><p>This report describes the molecular pharmacological properties of LR-B/081 (methyl 2-[[4-butyl-2-methyl-6-oxo-5-[ [2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-1 (6H)-pyrimidinyl]methyl]-3-thiophenecarboxilate), a novel non-peptide angiotensin II receptor antagonist. This compound potently displaced [³H]angiotensin II from angiotensin AT₁ (<em>K</em>_i = 1.4 nM, rat adrenal cortex), but not from angiotensin AT₂ (<em>K</em>_i &gt; 1 <em>ω</em>M, bovine cerebellar cortex) receptors and did not show affinity for other receptor systems (<em>K</em>_i &gt; 10 <em>ω</em>M). In saturation studies, LR-B/081 both increased <em>K</em>_<em>D</em> and decreased <em>B</em>_<em>max</em> values in a dose-dependent fashion. The rate of dissociation of [³H]angiotenin II from angiotensin AT₁ receptors was not affected by the presence of 1 ωM LR-B/081 and the association rate of [³H]angiotensin II was not decreased by the presence of 1 or 30 nM LR-B/081, indicating that the <em>B</em>_max reduction was not due to an allosteric interaction or to a delay in reaching the steady-state conditions. These data underline the complexity of the antagonistic nature of LR-B/081, presenting features of both competitive and noncompetitive antagonism.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 151-156"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90028-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19555741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide interacts with the dopamine transporter in rat brain synaptosomes","authors":"Andrew D. Campbell ,&nbsp;Daniel E. Womer ,&nbsp;Jay R. Simon","doi":"10.1016/0922-4106(95)90029-2","DOIUrl":"10.1016/0922-4106(95)90029-2","url":null,"abstract":"<div><p>The ability of the 5-HT₃ receptor agonist 1-(<em>m</em>-chlorophenyl)-biguanide to bind to the dopamine transporter and inhibit [³H]dopamine uptake was investigated in rat brain synaptosomes from the nucleus accumbens and caudate putamen. Competitive displacement experiments showed that 1-(<em>m</em>-chlorophenyl)-biguanide inhibited the binding of [³H]GBR-12935 in a biphasic manner (IC₅₀ values of 0.4 and 2.0 μM [high affinity] and 34.8 and 52.7 μM [low affinity] for caudate putamen and nucleus accumbens, respectively), and the high affinity binding site differed between brain regions. Serotonin was ineffective at competing for [³H]GBR-12935 binding, while the selective 5-HT₃ receptor antagonist ICS 205–930 exhibited an IC₅₀ &gt; 100 <em>μ</em>M. The maximum density of [³H]GBR-12935 binding sites was more than two-fold greater in the caudate putamen than in the nucleus accumbens (6.9 vs. 2.7 pmol/mg protein), and <em>K</em>_D values were similar (4.7 and 4.2 nM). 1-(<em>m</em>-chlorophenyl)-biguanide was able to inhibit [³H]dopamine uptake into synaptosomes of both brain regions, however it was significantly more potent in the caudate putamen (IC₅₀: 5.1 vs. 6.5 μM). The results demonstrate that some of the reported dopamine releasing effects of 1-(<em>m</em>-chlorophenyl)-biguanide may be due in part to activity at the dopamine transporter, and further suggest a possible difference in dopamine uptake parameters between the caudate putamen and nucleus accumbens.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 2","pages":"Pages 157-162"},"PeriodicalIF":0.0,"publicationDate":"1995-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90029-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19555742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}