THE ATYPICAL ANTIPSYCHOTIC PROFILE OF NRA0045, A NOVEL DOPAMINE D-4 AND 5-HYDROXYTRYPTAMINE(2A) RECEPTOR ANTAGONIST, IN RATS

1 The atypical antipsychotic profile of fluorophenyl)-5-[1-[4-(4-fluor ophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dop amine 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 (ED50 3.7 mg kg(-1)) , haloperidol (ED50 0.1 mg kg(-1)) and chlorpromazine (ED50 0.9 mg kg( -1)), whereas inhibition of this type of behaviour induced by i.p. adm inistration of NRA0045, at doses up to 10 mg kg(-1), did not exceed 50 %. 3 Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg( -1), i.p.) in rats (a model of antipsychotic activity) was dose-depend ently antagonized by NRA0045 (ED50 0.4 mg kg(-1), i.p., and 0.3 mg kg( -1), p.o., respectively), clozapine (ED50 0.3 mg kg(-1), i.p. and 0.8 mg kg(-1), p.o., respectively), haloperidol (ED50 0.02 mg kg(-1) i.p. and 0.1 mg kg(-1), p.o., respectively), chlorpromazine (ED50 0.3 mg kg (-1), i.p. and 3.3 mg kg(-1), p.o., respectively). In contrast, the MA P (3 mg kg(-1), i.v.)-induced stereotyped behaviour in rats (a model o f extrapyramidal symptoms) was not affected by NRA0045 or clozapine, a t the highest dose given (30 mg kg(-1), i.p.). Haloperidol (ED50 0.3 m g kg(-1) i.p.) and chlorpromazine (ED50 4.8 mg kg(-1), i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine s electively blocked behaviour associated with activation of the mesolim bic/mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4 Extracellular single-unit recording studies demonstrated t hat MAP (1 mg kg(-1), i.v.) decreased the firing rate in the substanti a nigra (A9) and ventral tegmental area (A10) dopamine neurones in ana esthetized rats. NRA0045 completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 0.1 mg kg(-1), i.v.), whereas the inhibitory effects of MAP on A9 dopamine neurones were not affected by NRA0045, in doses up to 1 mg kg(-1) (i.v.). Clozapine completely reve rsed the inhibitory effects of MAP on A10 dopamine neurones (ED50 1.9 mg kg(-1), i.v.) and on A9 dopamine neurones (ED50 2.5 mg kg(-1), i.v. ). Haloperidol completely reversed the inhibitory effects of MAP on A1 0 (ED50 0.03 mg kg(-1), i.v.) and on A9 dopamine neurones (0.02 mg kg( -1), i.v.). NRA0045, like clozapine. was more potent in reversing the effects of MAP on A10 than A9 dopamine neurones. 5 Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disrupti on of PPI in rats by apomorphine (0.5 mg kg(-1), s.c.) was reversed si gnificantly by NRA0045 (3 mg kg(-1), i.p.), clozapine (3 mg kg(-1), i. p.) and haloperidol (0.3 mg kg(-1), i.p.). 6 Phencyclidine (PCP) elici ts predominantly psychotic symptoms in normal humans and in schizophre nics. NRA0045 (0.03-0.3 mg kg(-1), i.p.) and clozapine (0.1-1 mg kg(-1 ), i.p.) significantly and dose-dependently shortened the PCP (1.25 mg kg(-1), i.p.)-induced prolonged swimming latency in rats in a water m aze task, whereas haloperidol (0.01-0.1 mg kg(-1), i.p.) did not signi ficantly alter swimming latency. 7 These findings suggest that NRA0045 may have unique antipsychotic activities without the liability of mot or side effects typical of classical antipsychotics.