The atypical antipsychotic profile of NRA0045, a novel dopamine D₄ and 5‐hydroxytryptamine_2A receptor antagonist, in rats

Abstract

1 The atypical antipsychotic pro®le of (R)-(+)-2-amino-4-(4-¯uorophenyl)-5-[1-[4-(4-¯uorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D 4 and 5-hydroxytryptamine (5-HT) 2A receptor antagonist, was examined in rats. 2 Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED 50 3.7 mg kg 71 ), haloperidol (ED 50 0.1 mg kg 71 ) and chlorpromazine (ED 50 0.9 mg kg 71 ), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg 71 , did not exceed 50%. 3 Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg 71 , i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED 50 0.4 mg kg 71 , i.p., and 0.3 mg kg 71 , p.o., respectively), clozapine (ED 50 0.3 mg kg 71 , i.p. and 0.8 mg kg 71 , p.o., respectively), haloperidol (ED 50 0.02 mg kg 71 , i.p. and 0.1 mg kg 71 , p.o., respectively), chlorpromazine (ED 50 0.3 mg kg 71 , i.p. and 3.3 mg kg 71 , p.o., respectively). In contrast, the MAP (3 mg kg 71 , i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not a ected by NRA0045 or clozapine, at the highest dose given (30 mg kg 71 , i.p.). Haloperidol (ED 50 0.3 mg kg 71 , i.p.) and chlorpromazine (ED 50 4.8 mg kg 71 , i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/ mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4 Extracellular single-unit recording studies demonstrated that MAP (1 mg kg 71 , i.v.) decreased the ®ring rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 0.1 mg kg 71 , i.v.), whereas the inhibitory e ects of MAP on A9 dopamine neurones were not a ected by NRA0045, in doses up to 1 mg kg 71 (i.v.). Clozapine completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 1.9 mg kg 71 , i.v.) and on A9 dopamine neurones (ED 50 2.5 mg kg 71 , i.v.). Haloperidol completely reversed the inhibitory e ects of MAP on A10 (ED 50 0.03 mg kg 71 , i.v.) and on A9 dopamine neurones (0.02 mg kg 71 , i.v.). NRA0045, like clozapine, was more potent in reversing the e ects of MAP on A10 than A9 dopamine neurones. 5 Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg 71 , s.c.) was reversed signi®cantly by NRA0045 (3 mg kg 71 , i.p.), clozapine (3 mg kg 71 , i.p.) and haloperidol (0.3 mg kg 71 , i.p.). 6 Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03 ± 0.3 mg kg 71 , i.p.) and clozapine (0.1 ± 1 mg kg 71 , i.p.) signi®cantly and dose-dependently shortened the PCP(1.25 mg kg 71 , i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (...

Effects of NRA0045, a novel potent antagonist at dopamine D4, 5-HT2A, and ?1 adrenaline receptors, and NRA0160, a selective D4 receptor antagonist, on phencyclidine-induced behavior and glutamate release in rats

“…Neural substrate of PCP-induced abnormal behavior NRA0045 and clozapine each effectively inhibited not only PCP-induced hyperlocomotion but also stereotypy and ataxia, although each drug has been reported effectively to block methamphetamine-induced hyperlocomotion, but not stereotypy (Okuyama et al 1997a(Okuyama et al , 1997b. Amphetamine-induced hyperlocomotion is closely related to the neuronal activity in the nucleus accumbens (Kelly et al 1975).…”

“…A novel thiazole derivative, NRA0045, which potently blocks not only dopamine D 4 receptors but also 5-HT 2A and a 1 -adrenaline receptors, inhibits methamphetamineinduced hyperlocomotion and PCP-induced cognitive dysfunction such as the prolongation of swimming latency in the water maze task (Okuyama et al 1997a(Okuyama et al , 1997b. Although another novel thiazole derivative, NRA0160, that selectively blocks dopamine D 4 receptors, inhibits PCP-induced prolongation of swimming latency, this agent weakly attenuates methamphetamine-induced hyperlocomotion (Okuyama et al 1999).…”

PHNO, a selective dopamine D 2 receptor agonist, does not reduce prepulse inhibition of the startle reflex in rats

“…Appendix -extended list of papers referring to drug effects on PPI Apomorphine: Mansbach et al 1988;Davis et al 1990;Keith et al 1991;Swerdlow et al 1991bSwerdlow et al , 1994Swerdlow et al , 1995Swerdlow et al , 1998bSchwarzkopf et al 1993, Swerdlow andGeyer 1993;Hoffman and Donovan 1994;Caine et al 1995;Campeau and Davis 1995;Ellenbroek et al 1995;Lipska et al 1995;Taylor et al 1995;Varty and Higgins 1995;Young et al 1995;Zhang et al 1995;Hauber and Koch 1997;Okuyama et al 1997;Druhan et al 1998;Hart et al 1998;Kretschmer and Koch 1998;Martin-Iverson 1999;Rigdon 1999;Varty and Higgins 1999 Amphetamine: Mansbach et al 1988;Swerdlow et al 1990Swerdlow et al , 1991bHijzen et al 1991;Ott and Mandel 1995;Wan et al 1995;Zhang et al 1995;Feifel and Minor 1997;Feifel et al 1997aFeifel et al , 1997bFeifel et al , 1999Curzon and Decker 1998;Druhan et al 1998;Mintz et al 1998;Zhang et al 1998 Dopamine uptake blockers: …”

Dopamine D4 receptors: significance for molecular psychiatry at the millennium

“…In addition, both compounds attenuated hyperlocomotion induced by DA agonists and significantly reversed apomorphine-induced disruption of PPI. 96,97,116,117 The findings suggest that these compounds may have potential for clinical psychotropic activity with a low risk of extrapyramidal motor effects associated with effective D 2 receptor blockade that seems to be characteristic of all typical neuroleptics. 1,17 Surprisingly, preliminary clinical trials with at least two agents with D 4 -over-D 2 selectivity have failed to indicate any evidence of antipsychotic benefits.…”