F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. II. Activity in models of positive symptoms of schizophrenia

Abstract

Background and purpose: F15063 is a high affinity D(2)/D(3) antagonist, D(4) partial agonist, and high efficacy 5-HT(1A) 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 (ED(50)=0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT(1A) agonism, did not produce (ED(50)>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: ED(50) >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).

Figure 1

Antagonism by F15063 of climbing and sniffing behaviours induced by apomorphine in mice. Each symbol represents the mean behavioural score (±s.e.m.) obtained during observation periods (10 s every min, from 55 to 65 min after F15063 administration). Apomorphine (2.5 mg kg⁻1 s.c.) was injected 45 min after F15063. ^**P<0.01, compared with the vehicle/apomorphine group (scores were 9.45±0.2 and 9.94±0.04 for climbing and sniffing, respectively, n=84), Bonferroni's post hoc tests following significant one-way ANOVA (climbing (F(5,123)=139.6, P<0.0001)) and sniffing (F(5,123)=600.6, P<0.0001). N=7 mice per group.

Figure 2

Antagonism by F15063 of stereotypies induced by methylphenidate in rats after i.p. (a) or p.o. (b) administration. Each symbol represents the percentage of rats showing a gnawing score less than 9, or a complete normalization of stereotyped behaviour induced by 40 mg kg⁻¹ i.p. methylphenidate, administered 30 min after F15063 or vehicle. For both panels, N=7 rats per group.

Figure 3

Reduction by F15063 of two-way active avoidance behaviour in rats. Each symbol represents the mean (±s.e.m.) number of CARs (out of a maximum of 30) or EFRs. F15063 or vehicle was administered 60 min before the start of the session. ^**P<0.01, compared with the vehicle-treated group (mean represented by the upper dotted line) for CAR; ^##P<0.01, compared with the vehicle-treated group (mean represented by the lower dotted line) for EFR, Bonferroni's post hoc tests following significant one-way ANOVA (CAR (F(4,52)=90.8, P<0.0001); EFR (F(4,52)=25.2, P<0.0001)). N=7 rats per group.

Figure 4

Reversal by F15063 of hyperlocomotor activity induced by d-amphetamine (a) or ketamine (b) in rats. Each symbol represents the mean (±s.e.m.) number of infrared beam interruptions recorded 16–75 min following an s.c. injection of d-amphetamine (0.63 mg kg⁻¹) or ketamine (40 mg kg⁻¹). Bottom and top dotted lines represent the average locomotor score for vehicle- and psychotomimetic-injected rats, respectively. ^(*)P=0.05, ^**P<0.01, compared with the vehicle/d-amphetamine group, ^(#)P=0.06, ^##P<0.01, compared with the vehicle/ketamine group, Bonferroni's post hoc tests following significant one-way ANOVA (versus amphetamine (F(4,133)=10.6, P<0.0001); versus ketamine (F(4,137)=4.3, P<0.001)). N=7 rats per group.

Figure 5

Diminution by F15063 of a deficit of the PPI of the startle reflex induced by apomorphine in rats. Each symbol represents the mean (±s.e.m.) percentage of PPI, recorded 60 min after i.p. injection of F15063 or vehicle. Apomorphine (0.63 mg kg⁻¹ s.c.) was administered 15 min pre-test. ^**P<0.01, compared with the vehicle/apomorphine vehicle control group, Dunnett's post hoc tests following significant one-way ANOVA (F(6,231)=5.9, P<0.001). N=13 rats per group.

Figure 6

Lack of cataleptogenic activity of F15063 in rats and mice is due to activation of 5-HT_1A receptors: Interaction with the 5-HT_1A receptor antagonist WAY100,635. Each symbol represents the mean (±s.e.m.) time spent in a cataleptic position in the CLP (a) and in the bar test in rats (b) and mice (c), measured 60 min post F15063 administration. WAY100,635 (WAY) was injected s.c. (0.63 mg kg⁻¹) 15 min before F15063. ^**P<0.01, compared with the vehicle (Veh)/F15063 group at the corresponding dose of F15063, Bonferroni's post hoc tests following significant two-way ANOVA (significant treatment, pretreatment and interaction factors: all F's>5.9, all P's<0.0001). N=7 rats or mice per group.

Figure 7

Lack of cataleptogenic activity of F15063 in rats is preserved following repeated treatment. Interaction with the 5-HT_1A receptor antagonist WAY100,635. Each symbol represents the mean (±s.e.m.) time spent in a cataleptic position in the CLP (a) and in the bar test (b) in rats. F15063 (40 mg kg⁻¹) or vehicle were administered p.o. daily for 4 consecutive days and, on the 5th day all rats received an acute challenge with the same dose of F15063 60 min before testing. Vehicle or WAY100,635 (0.63 mg kg⁻¹ s.c.) were administered 15 min before the acute challenge with F15063. ^**P<0.01, Newman–Keuls post hoc test following significant two-way ANOVA (CLP (F(1,19)=19.1, P<0.001); bar test (F(1,19)=21.6, P<0.001)). N=7 rats per group.

Figure 8

F15063 does not produce the serotonin syndrome in rats at ‘therapeutically relevant' doses. Each symbol represents the percentage of rats showing FPT (a), LLR (b) and FBP (c). Behavioural observations were made from 10 to 20 min and from 55 to 65 min post i.p. or p.o. administration of F15063. N=5 rats per group. (▪) Data for 8-OH-DPAT (p.o. administration), from Koek et al. (1998).