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Titolo:
ENDOGENOUS DOPAMINE LIMITS THE BINDING OF ANTIPSYCHOTIC-DRUGS TO D-3 RECEPTORS IN THE RAT-BRAIN - A QUANTITATIVE AUTORADIOGRAPHIC STUDY
Autore:
SCHOTTE A; JANSSEN PFM; BONAVENTURE P; LEYSEN JE;
Indirizzi:
JANSSEN RES FDN,DEPT BIOCHEM PHARMACOL,TURNHOUTSEWEG 30 B-2340 BEERSEBELGIUM
Titolo Testata:
Histochemical Journal
fascicolo: 11, volume: 28, anno: 1996,
pagine: 791 - 799
SICI:
0018-2214(1996)28:11<791:EDLTBO>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
INVITRO BINDING; MESSENGER-RNA; CLONING; VISUALIZATION; LOCALIZATION; AFFINITY; LIGAND; GENE; D1; D3;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
25
Recensione:
Indirizzi per estratti:
Citazione:
A. Schotte et al., "ENDOGENOUS DOPAMINE LIMITS THE BINDING OF ANTIPSYCHOTIC-DRUGS TO D-3 RECEPTORS IN THE RAT-BRAIN - A QUANTITATIVE AUTORADIOGRAPHIC STUDY", Histochemical Journal, 28(11), 1996, pp. 791-799

Abstract

[H-3]7-hydroxy-N,N-di-n-propyl-2-aminotetralin was used as a radioligand for the autoradiographic measurements of dopamine D-3 receptors inrat and human brain. Preincubation of the brain sections was necessary to obtain binding of the radioligand in the islands of Calleja and in the nucleus accumbens, but not in cerebellar lobules 9/10 of the rat. D-3 receptors were also totally occluded in unwashed sections of thehuman striatum. The radioligand binding to D-3 receptors was maximal after preincubating the sections for at least 10 min. Pretreatment of the animals with reserpine or tetrabenazine, which results in a severedepletion of endogeneous monoamines, strongly reduces the occlusion of D-3 receptors in unwashed brain sections. The occlusion of dopamine D-3 receptors in brain sections suggests that the in vivo access to D-3 receptors may be locally inhibited by endogenous dopamine. The in vitro binding affinities of 12 antipsychotic drugs for D-2 and D-3 receptors were evaluated in competition binding experiments, using both ratand cloned human receptors. Most of the compounds showed only a slightly lower affinity for D-3 than for D-2 receptors in vitro. Affinitiesof the antipsychotic drugs for cloned human D-2L and D-3 receptors were very close to their affinities for the rat receptors. In vivo occupancy of these receptors in the rat brain was measured ex vivo by quantitative autoradiography, 2 hours after subcutaneous drug administration. For most compounds, occupancy of D-3 receptors, as compared to D-2 receptor occupancy, was lower than expected from the corresponding in vivo affinity ratios. For the new antipsychotic risperidone, in vine occupancy of D-3 receptors was measured both in the islands of Calleja and in the cerebellar lobules 9/10. This compound was three times lesspotent for the occupancy of D-3 receptors in the islands of Calleja than in the cerebellum, an area lacking endogenous dopamine (ED(50) = 28 and 10 mg kg(-1), respectively). Based on the observations in the rat brain, it may reasonably be supposed that therapeutic dosages of antipsychotic drugs will induce in patients only a minor occupancy of D-3receptors in brain areas containing high dopamine concentrations. Therole of dopamine D-3 receptors as a target of antipsychotic drugs maytherefore be less important than previously thought.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 06:25:44