Dopamine receptor antagonist properties of S 14506, 8-OH-DPAT, raclopride and clozapine in rodents

Abstract

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.