Dopamine D1 receptor desensitization profile in MPTP-lesioned primates
Identifieur interne : 003F00 ( Main/Exploration ); précédent : 003E99; suivant : 003F01Dopamine D1 receptor desensitization profile in MPTP-lesioned primates
Auteurs : P. J. Blanchet [Canada] ; R. Grondin [Canada] ; P. J. Bedard [Canada] ; K. Shiosaki [États-Unis] ; D. R. Britton [États-Unis]Source :
- European journal of pharmacology [ 0014-2999 ] ; 1996.
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- Pascal (Inist)
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- topic : Singe.
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Abstract
The motor effects of dopamine D1 receptor activation and the optimal way to stimulate these receptors were studied in a primate model of parkinsonism induced by the neurotoxin 1-methy1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), using 2 selective full dopamine D1 receptor agonists : A-77636 ([1R,3S] 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride), and SKF 82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide). A-77636 was administered to one group of primed monkeys (N = 4) previously treated with levodopa and other dopamine receptor agonists, while SKF 82958 was given to another group of drug-naive monkeys (N= 3). These drugs have different durations of efficacy, lasting > 20 h and approximately 1 h, respectively, and were administered once daily (A-77636) or thrice daily (SKF 82958) for 7 days. Both drugs demonstrated excellent antiparkinsonian efficacy and locomotor stimulation. However, a rapid, functionally important, homologous (selective for D1 receptor agonists) desensitization process took place as early as on the second day with the longer-acting drug and a dose escalation of A-77636 failed to restore the initial benefit. Thrice daily dosing at a 4-h interval with the short-acting agent SKF 82958 maintained the maximal antiparkinsonian response but some shortening in the duration of response was observed after several days. These behavioral results show that dopamine D1 receptors are susceptible to desensitization after prolonged occupancy and can be desensitized profoundly and independently of dopamine D2 receptors in vivo in this model. Potent dopamine D1 receptor agonists with an intermediate half-life may prove to be better adjuncts in the treatment of Parkinson's disease. Clinical entities with pathologically enhanced dopamine D1 receptor-linked neural transmission might eventually also benefit from such desensitization.
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J." last="Blanchet">P. J. Blanchet</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurobiology Research Centre, Hôpital de l'Enfant-Jésus</s1><s2>Québec City (Québec)</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec City (Québec)</wicri:noRegion></affiliation></author><author><name sortKey="Grondin, R" sort="Grondin, R" uniqKey="Grondin R" first="R." last="Grondin">R. Grondin</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurobiology Research Centre, Hôpital de l'Enfant-Jésus</s1><s2>Québec City (Québec)</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec City (Québec)</wicri:noRegion></affiliation></author><author><name sortKey="Bedard, P J" sort="Bedard, P J" uniqKey="Bedard P" first="P. J." last="Bedard">P. J. Bedard</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurobiology Research Centre, Hôpital de l'Enfant-Jésus</s1><s2>Québec City (Québec)</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec City (Québec)</wicri:noRegion></affiliation></author><author><name sortKey="Shiosaki, K" sort="Shiosaki, K" uniqKey="Shiosaki K" first="K." last="Shiosaki">K. Shiosaki</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neuroscience Research (D-47U), Pharmaceutical Products Division, Abbott Laboratories</s1><s2>Abbott Park, IL</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Abbott Park, IL</wicri:noRegion></affiliation></author><author><name sortKey="Britton, D R" sort="Britton, D R" uniqKey="Britton D" first="D. R." last="Britton">D. R. Britton</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neuroscience Research (D-47U), Pharmaceutical Products Division, Abbott Laboratories</s1><s2>Abbott Park, IL</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Abbott Park, IL</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">European journal of pharmacology</title><title level="j" type="abbreviated">Eur. j. pharmacol.</title><idno type="ISSN">0014-2999</idno><imprint><date when="1996">1996</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">European journal of pharmacology</title><title level="j" type="abbreviated">Eur. j. pharmacol.</title><idno type="ISSN">0014-2999</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Administration schedule</term><term>Agonist</term><term>Animal</term><term>Antiparkinson agent</term><term>Chemotherapy</term><term>D1 Dopamine receptor</term><term>Desensitization</term><term>Monkey</term><term>Parkinson disease</term><term>Subcutaneous administration</term><term>Time response relation</term><term>Treatment efficiency</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Agoniste</term><term>Récepteur dopaminergique D1</term><term>Antiparkinsonien</term><term>Parkinson maladie</term><term>Animal</term><term>Singe</term><term>Voie souscutanée</term><term>Chimiothérapie</term><term>Efficacité traitement</term><term>Relation temps réponse</term><term>Rythme administration</term><term>Désensibilisation</term><term>A 77636</term><term>SKF 82958</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Singe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The motor effects of dopamine D<sub>1</sub> receptor activation and the optimal way to stimulate these receptors were studied in a primate model of parkinsonism induced by the neurotoxin 1-methy1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), using 2 selective full dopamine D<sub>1</sub> receptor agonists : A-77636 ([1R,3S] 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride), and SKF 82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide). A-77636 was administered to one group of primed monkeys (N = 4) previously treated with levodopa and other dopamine receptor agonists, while SKF 82958 was given to another group of drug-naive monkeys (N= 3). These drugs have different durations of efficacy, lasting > 20 h and approximately 1 h, respectively, and were administered once daily (A-77636) or thrice daily (SKF 82958) for 7 days. Both drugs demonstrated excellent antiparkinsonian efficacy and locomotor stimulation. However, a rapid, functionally important, homologous (selective for D<sub>1</sub> receptor agonists) desensitization process took place as early as on the second day with the longer-acting drug and a dose escalation of A-77636 failed to restore the initial benefit. Thrice daily dosing at a 4-h interval with the short-acting agent SKF 82958 maintained the maximal antiparkinsonian response but some shortening in the duration of response was observed after several days. These behavioral results show that dopamine D<sub>1</sub> receptors are susceptible to desensitization after prolonged occupancy and can be desensitized profoundly and independently of dopamine D<sub>2</sub> receptors in vivo in this model. Potent dopamine D<sub>1</sub> receptor agonists with an intermediate half-life may prove to be better adjuncts in the treatment of Parkinson's disease. Clinical entities with pathologically enhanced dopamine D<sub>1</sub> receptor-linked neural transmission might eventually also benefit from such desensitization.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Blanchet, P J" sort="Blanchet, P J" uniqKey="Blanchet P" first="P. J." last="Blanchet">P. J. Blanchet</name></noRegion><name sortKey="Bedard, P J" sort="Bedard, P J" uniqKey="Bedard P" first="P. J." last="Bedard">P. J. Bedard</name><name sortKey="Grondin, R" sort="Grondin, R" uniqKey="Grondin R" first="R." last="Grondin">R. Grondin</name></country><country name="États-Unis"><noRegion><name sortKey="Shiosaki, K" sort="Shiosaki, K" uniqKey="Shiosaki K" first="K." last="Shiosaki">K. Shiosaki</name></noRegion><name sortKey="Britton, D R" sort="Britton, D R" uniqKey="Britton D" first="D. R." last="Britton">D. R. Britton</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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