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 : 002945 ( Main/Exploration ); précédent : 002944; suivant : 002946The 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 [Allemagne] ; Oleh Hornykiewicz [Autriche] ; Walter Kobinger [Autriche] ; Ludwig Pichler [Autriche] ; Christian Pifl [Autriche] ; Günter Schingnitz [Allemagne]Source :
- 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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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><affiliations><list><country><li>Allemagne</li><li>Autriche</li></country></list><tree><country name="Allemagne"><noRegion><name sortKey="Hinzen, Dieter" sort="Hinzen, Dieter" uniqKey="Hinzen D" first="Dieter" last="Hinzen">Dieter Hinzen</name></noRegion><name sortKey="Schingnitz, Gunter" sort="Schingnitz, Gunter" uniqKey="Schingnitz G" first="Günter" last="Schingnitz">Günter Schingnitz</name></country><country name="Autriche"><noRegion><name sortKey="Hornykiewicz, Oleh" sort="Hornykiewicz, Oleh" uniqKey="Hornykiewicz O" first="Oleh" last="Hornykiewicz">Oleh Hornykiewicz</name></noRegion><name sortKey="Kobinger, Walter" sort="Kobinger, Walter" uniqKey="Kobinger W" first="Walter" last="Kobinger">Walter Kobinger</name><name sortKey="Pichler, Ludwig" sort="Pichler, Ludwig" uniqKey="Pichler L" first="Ludwig" last="Pichler">Ludwig Pichler</name><name sortKey="Pifl, Christian" sort="Pifl, Christian" uniqKey="Pifl C" first="Christian" last="Pifl">Christian Pifl</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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