Dopamine receptor antagonist properties of S 14506, 8-OH-DPAT, raclopride and clozapine in rodents.
S 14506 (1-[-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piper azine hydrochloride), 8-OH-DPAT ((+/-)-8-hydroxydipropylaminotetralin hydrobromide), clozapine and raclopride were compared in some behavioural models able to characterize dopamine antagonist properties. In mice treated with apomorphine (0.75 mg/kg, s.c.), stereotyped climbing and sniffing were dose dependently antagonized by S 14506, by clozapine and by raclopride, but were virtually not modified by 8-OH-DPAT. Stereotyped climbing and sniffing induced by (+)-amphetamine (1.25 mg/kg, s.c.) in mice treated with L-DOPA (L-3,4-dihydroxyphenylalanine 75 mg/kg, associated with benserazide, i.p.) were also dose dependently antagonized by S 14506 and by raclopride, but were only partially antagonized by clozapine and unaffected by 8-OH-DPAT. Grooming behaviour induced by SK&F 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, 1.87 mg/kg, s.c.) in mice was inhibited by low doses of S 14506 and of clozapine, and by relatively high doses of 8-OH-DPAT and of raclopride. The decreased grooming behaviour observed in apomorphine-treated mice was partly antagonized by high dose of raclopride but was significantly potentiated by S 14506, 8-OH-DPAT and clozapine. Raclopride produced the same effect in mice treated with (+)-amphetamine and L-DOPA. In rats treated with apomorphine (0.6 mg/kg, s.c.), sniffing was dose dependently antagonized by S 14506, by raclopride and by clozapine, but not by 8-OH-DPAT. Again, whereas increasing doses of raclopride allowed grooming to reappear in apomorphine (0.6 mg/kg)-treated rats, S 14506, 8-OH-DPAT and clozapine did not. Raclopride induced catalepsy in rats, whereas like clozapine, S 14506 was virtually ineffective. All the tested compounds inhibited in vitro [3H]raclopride binding in rat striatum (raclopride > S 14506 > clozapine > 8-OH-DPAT), whereas only clozapine inhibited [3H]SCH 23390 binding. Finally, S 14506 inhibited the in vivo binding of [3H]raclopride in striatum and olfactory bulbs, but did not affect the striatal in vivo binding of [3H]SCH 23390. From these data, it appears that like raclopride, S 14506 displays dopamine antagonist properties by blocking dopamine D2 receptors. However, the psychopharmacological profile of S 14506 is closer to that of clozapine than to that of raclopride, probably as a result of its actions at 5-HT receptors.
Protais
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Laboratoire de Physiologie (VACOMED), U.F.R. de Médecine-Pharmacie de Rouen, Saint Etienne Rouvray, France.
Chagraoui
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A
Arbaoui
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Mocaër
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E
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced / Q000473:pathology; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006120:Grooming / Q000187:drug effects; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D020891:Raclopride; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012457:Salicylamides / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects
D001549:Benzamides; D001552:Benzazepines; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C092824:1-((4-fluorobenzoylamino)ethyl)-4-(7-methoxy-1-naphthyl)piperazine hydrochloride; D020891:Raclopride; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003024:Clozapine