The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment
Identifieur interne : 000520 ( Main/Corpus ); précédent : 000519; suivant : 000521The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment
Auteurs : Dieter Hinzen ; Oleh Hornykiewicz ; Walter Kobinger ; Ludwig Pichler ; Christian Pifl ; Günter SchingnitzSource :
- European Journal of Pharmacology [ 0014-2999 ] ; 1986.
Abstract
B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at α2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2–20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1–10 mg/kg s.c.) which elecited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02–2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2–2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5–10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02–1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 μg/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 μg/kg i.m. It is concluded that the property of B-HT 920 to stimulate the ‘denervated’ supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.
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DOI: 10.1016/0014-2999(86)90517-0
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Austria</mods:affiliation></affiliation></author><author><name sortKey="Kobinger, Walter" sort="Kobinger, Walter" uniqKey="Kobinger W" first="Walter" last="Kobinger">Walter Kobinger</name><affiliation><mods:affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</mods:affiliation></affiliation></author><author><name sortKey="Pichler, Ludwig" sort="Pichler, Ludwig" uniqKey="Pichler L" first="Ludwig" last="Pichler">Ludwig Pichler</name><affiliation><mods:affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</mods:affiliation></affiliation></author><author><name sortKey="Pifl, Christian" sort="Pifl, Christian" uniqKey="Pifl C" first="Christian" last="Pifl">Christian Pifl</name><affiliation><mods:affiliation>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</mods:affiliation></affiliation></author><author><name sortKey="Schingnitz, Gunter" sort="Schingnitz, Gunter" uniqKey="Schingnitz G" first="Günter" last="Schingnitz">Günter Schingnitz</name><affiliation><mods:affiliation>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:8CF580BDA070B84EE036E605C3A49CE60754CDAC</idno><date when="1986" year="1986">1986</date><idno type="doi">10.1016/0014-2999(86)90517-0</idno><idno type="url">https://api.istex.fr/document/8CF580BDA070B84EE036E605C3A49CE60754CDAC/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000520</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment</title><author><name sortKey="Hinzen, Dieter" sort="Hinzen, Dieter" uniqKey="Hinzen D" first="Dieter" last="Hinzen">Dieter Hinzen</name><affiliation><mods:affiliation>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</mods:affiliation></affiliation></author><author><name sortKey="Hornykiewicz, Oleh" sort="Hornykiewicz, Oleh" uniqKey="Hornykiewicz O" first="Oleh" last="Hornykiewicz">Oleh Hornykiewicz</name><affiliation><mods:affiliation>To whom all correspondence should be addressed.</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</mods:affiliation></affiliation></author><author><name sortKey="Kobinger, Walter" sort="Kobinger, Walter" uniqKey="Kobinger W" first="Walter" last="Kobinger">Walter Kobinger</name><affiliation><mods:affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</mods:affiliation></affiliation></author><author><name sortKey="Pichler, Ludwig" sort="Pichler, Ludwig" uniqKey="Pichler L" first="Ludwig" last="Pichler">Ludwig Pichler</name><affiliation><mods:affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</mods:affiliation></affiliation></author><author><name sortKey="Pifl, Christian" sort="Pifl, Christian" uniqKey="Pifl C" first="Christian" last="Pifl">Christian Pifl</name><affiliation><mods:affiliation>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</mods:affiliation></affiliation></author><author><name sortKey="Schingnitz, Gunter" sort="Schingnitz, Gunter" uniqKey="Schingnitz G" first="Günter" last="Schingnitz">Günter Schingnitz</name><affiliation><mods:affiliation>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Pharmacology</title><title level="j" type="abbrev">EJP</title><idno type="ISSN">0014-2999</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1986">1986</date><biblScope unit="volume">131</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="75">75</biblScope><biblScope unit="page" to="86">86</biblScope></imprint><idno type="ISSN">0014-2999</idno></series><idno type="istex">8CF580BDA070B84EE036E605C3A49CE60754CDAC</idno><idno type="DOI">10.1016/0014-2999(86)90517-0</idno><idno type="PII">0014-2999(86)90517-0</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0014-2999</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at α2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2–20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1–10 mg/kg s.c.) which elecited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02–2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2–2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5–10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02–1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 μg/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 μg/kg i.m. It is concluded that the property of B-HT 920 to stimulate the ‘denervated’ supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>Dieter Hinzen</name><affiliations><json:string>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</json:string></affiliations></json:item><json:item><name>Oleh Hornykiewicz</name><affiliations><json:string>To whom all correspondence should be addressed.</json:string><json:string>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</json:string></affiliations></json:item><json:item><name>Walter Kobinger</name><affiliations><json:string>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</json:string></affiliations></json:item><json:item><name>Ludwig Pichler</name><affiliations><json:string>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</json:string></affiliations></json:item><json:item><name>Christian Pifl</name><affiliations><json:string>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</json:string></affiliations></json:item><json:item><name>Günter Schingnitz</name><affiliations><json:string>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-4,5-d]azepine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Dopamine receptors</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Autoreceptor agonists</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Postsynaptic supersensitivity</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MPTP</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item></subject><language><json:string>eng</json:string></language><abstract>B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at α2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2–20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1–10 mg/kg s.c.) which elecited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02–2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2–2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5–10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02–1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 μg/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 μg/kg i.m. It is concluded that the property of B-HT 920 to stimulate the ‘denervated’ supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.</abstract><qualityIndicators><score>8</score><pdfVersion>1.2</pdfVersion><pdfPageSize>548 x 742 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>2080</abstractCharCount><pdfWordCount>7527</pdfWordCount><pdfCharCount>39856</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>301</abstractWordCount></qualityIndicators><title>The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to 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level="a">The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>ELSEVIER</p></availability><date>1986</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment</title><author><persName><forename type="first">Dieter</forename><surname>Hinzen</surname></persName><affiliation>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</affiliation></author><author><persName><forename type="first">Oleh</forename><surname>Hornykiewicz</surname></persName><affiliation>To whom all correspondence should be addressed.</affiliation><affiliation>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</affiliation></author><author><persName><forename type="first">Walter</forename><surname>Kobinger</surname></persName><affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</affiliation></author><author><persName><forename type="first">Ludwig</forename><surname>Pichler</surname></persName><affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</affiliation></author><author><persName><forename type="first">Christian</forename><surname>Pifl</surname></persName><affiliation>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</affiliation></author><author><persName><forename type="first">Günter</forename><surname>Schingnitz</surname></persName><affiliation>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</affiliation></author></analytic><monogr><title level="j">European Journal of Pharmacology</title><title level="j" type="abbrev">EJP</title><idno type="pISSN">0014-2999</idno><idno type="PII">S0014-2999(00)X1060-6</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1986"></date><biblScope unit="volume">131</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="75">75</biblScope><biblScope unit="page" to="86">86</biblScope></imprint></monogr><idno type="istex">8CF580BDA070B84EE036E605C3A49CE60754CDAC</idno><idno type="DOI">10.1016/0014-2999(86)90517-0</idno><idno type="PII">0014-2999(86)90517-0</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1986</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at α2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2–20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1–10 mg/kg s.c.) which elecited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02–2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2–2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5–10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02–1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 μg/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 μg/kg i.m. It is concluded that the property of B-HT 920 to stimulate the ‘denervated’ supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-4,5-d]azepine</term></item><item><term>Dopamine receptors</term></item><item><term>Autoreceptor agonists</term></item><item><term>Postsynaptic supersensitivity</term></item><item><term>MPTP</term></item><item><term>Parkinson's disease</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1986-08-12">Registration</change><change when="1986">Published</change></revisionDesc></teiHeader></istex:fulltextTEI></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla"><item-info><jid>EJP</jid><aid>86905170</aid><ce:pii>0014-2999(86)90517-0</ce:pii><ce:doi>10.1016/0014-2999(86)90517-0</ce:doi><ce:copyright type="unknown" year="1986"></ce:copyright></item-info><head><ce:title>The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment</ce:title><ce:author-group><ce:author><ce:given-name>Dieter</ce:given-name><ce:surname>Hinzen</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>1</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Oleh</ce:given-name><ce:surname>Hornykiewicz</ce:surname><ce:cross-ref refid="COR1"><ce:sup>∗</ce:sup></ce:cross-ref><ce:cross-ref refid="AFF2"><ce:sup>2</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Walter</ce:given-name><ce:surname>Kobinger</ce:surname><ce:cross-ref refid="AFF3"><ce:sup>3</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Ludwig</ce:given-name><ce:surname>Pichler</ce:surname><ce:cross-ref refid="AFF3"><ce:sup>3</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Christian</ce:given-name><ce:surname>Pifl</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>2</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Günter</ce:given-name><ce:surname>Schingnitz</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>1</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</ce:textfn></ce:affiliation><ce:affiliation id="AFF3"><ce:label>c</ce:label><ce:textfn>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</ce:textfn></ce:affiliation><ce:correspondence id="COR1"><ce:label>∗</ce:label><ce:text>To whom all correspondence should be addressed.</ce:text></ce:correspondence></ce:author-group><ce:date-received day="15" month="5" year="1986"></ce:date-received><ce:date-accepted day="12" month="8" year="1986"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at <ce:italic>α</ce:italic><ce:inf>2</ce:inf>-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2–20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1–10 mg/kg s.c.) which elecited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02–2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2–2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5–10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02–1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D<ce:inf>2</ce:inf>-antagonist sulpiride but not by the D<ce:inf>1</ce:inf>-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 μg/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 μg/kg i.m. It is concluded that the property of B-HT 920 to stimulate the ‘denervated’ supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-4,5-d]azepine</ce:text></ce:keyword><ce:keyword><ce:text>Dopamine receptors</ce:text></ce:keyword><ce:keyword><ce:text>Autoreceptor agonists</ce:text></ce:keyword><ce:keyword><ce:text>Postsynaptic supersensitivity</ce:text></ce:keyword><ce:keyword><ce:text>MPTP</ce:text></ce:keyword><ce:keyword><ce:text>Parkinson's disease</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment</title></titleInfo><name type="personal"><namePart type="given">Dieter</namePart><namePart type="family">Hinzen</namePart><affiliation>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Oleh</namePart><namePart type="family">Hornykiewicz</namePart><affiliation>To whom all correspondence should be addressed.</affiliation><affiliation>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Walter</namePart><namePart type="family">Kobinger</namePart><affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ludwig</namePart><namePart type="family">Pichler</namePart><affiliation>Ernst-Boehringer-Institut für Arzneimittelforschung, Department of Pharmacology, Dr. Boehringergasse 5-11, A-1121 Wien, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Pifl</namePart><affiliation>University of Vienna, Institute of Biochemical Pharmacology, Borschkegasse 8a, A-1090 Wien, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Günter</namePart><namePart type="family">Schingnitz</namePart><affiliation>Boehringer Ingelheim KG., Department of Pharmacology, D-6507 Ingelheim am Rhein, F.R.G.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1986</dateIssued><dateValid encoding="w3cdtf">1986-08-12</dateValid><copyrightDate encoding="w3cdtf">1986</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at α2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2–20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1–10 mg/kg s.c.) which elecited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02–2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2–2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5–10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02–1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 μg/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 μg/kg i.m. It is concluded that the property of B-HT 920 to stimulate the ‘denervated’ supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.</abstract><subject><genre>Keywords</genre><topic>B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-4,5-d]azepine</topic><topic>Dopamine receptors</topic><topic>Autoreceptor agonists</topic><topic>Postsynaptic supersensitivity</topic><topic>MPTP</topic><topic>Parkinson's disease</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Pharmacology</title></titleInfo><titleInfo type="abbreviated"><title>EJP</title></titleInfo><genre type="Journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">19861112</dateIssued></originInfo><identifier type="ISSN">0014-2999</identifier><identifier type="PII">S0014-2999(00)X1060-6</identifier><part><date>19861112</date><detail type="volume"><number>131</number><caption>vol.</caption></detail><detail type="issue"><number>1</number><caption>no.</caption></detail><extent unit="issue pages"><start>1</start><end>162</end></extent><extent unit="pages"><start>75</start><end>86</end></extent></part></relatedItem><identifier type="istex">8CF580BDA070B84EE036E605C3A49CE60754CDAC</identifier><identifier type="DOI">10.1016/0014-2999(86)90517-0</identifier><identifier type="PII">0014-2999(86)90517-0</identifier><recordInfo><recordContentSource>ELSEVIER</recordContentSource></recordInfo></mods></metadata><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/8CF580BDA070B84EE036E605C3A49CE60754CDAC/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">PHARMACOLOGY & PHARMACY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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