F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties:: (II) Activity in models of positive symptoms of schizophrenia

Background and purpose: F15063 is a high affinity D-2/D-3 antagonist, D-4 partial agonist, and high efficacy 5-HT1A agonist, with little affinity ( 40-fold lower than for D-2 receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects. Experimental approach: Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and 'serotonin syndrome'. Key results: F15063 potently ( ED(50)s: 0.23 to 1.10 mg kg(-1) i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition ( PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing ( ED50 = 0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT1A agonism, did not produce ( ED50 > 40 mg kg(-1) i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome ( EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg(-1) p.o. Furthermore, F15063 did not induce the 'serotonin syndrome' in rats ( flat body posture and forepaw treading: ED50 > 32 mg kg(-1) i.p.). Conclusions and implications: F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia ( companion paper).