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

Abstract

Background and purpose: The D(2)/D(3) receptor antagonist, D(4) receptor partial agonist, and high efficacy 5-HT(1A) receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the 'serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia.

Experimental approach: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems.

Key results: Through 5-HT(1A) activation, F15063 partially alleviated (MED: 0.04 mg kg(-1)) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg(-1), F15063 reduced interaction by itself. F15063 (0.16 mg kg(-1)) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04-0.63 mg kg(-1)) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D(4) partial agonism, as it was blocked by the D(4) antagonist L745,870. Finally, F15063 up to 40 mg kg(-1) did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating.

Conclusions and implications: The balance of D(2)/D(3), D(4) and 5-HT(1A) receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.

Figure 1

F15063 attenuated a deficit of social interaction in rats produced by PCP. Each symbol/bar represents the mean (±s.e.m.) number of social interaction events between a dyad of rats. F15063 or vehicle was administered daily for 3 days in combination with a s.c. injection of either vehicle or 2.5 mg kg⁻¹ PCP. Social interaction (10 min observation period) was measured on the last (3rd) day of drug treatment, 45 min after the last injection. Statistical analysis: two-way ANOVA: F(9,132)=14.1, P<0.001, F(1,132)=815, P<0.001 and F(9,132)=6.7, P<0.001, for the F15063 dose, PCP treatment and F15063 dose × PCP treatment interaction, respectively. This two-way ANOVA was followed by separate one-way ANOVAs. (^*)P=0.05, ^*P<0.05, ^**P<0.01, versus vehicle for vehicle-treated rats, Bonferroni's post hoc test, following significant one-way ANOVA: F(9,69)=10.3, P<0.001. ^#P<0.05, ^##P<0.01, versus vehicle for PCP-treated rats, Bonferroni's post hoc test, following significant one-way ANOVA: F(9,69)=11.4, P<0.001. N=7–9 pairs of rats per group.

Figure 2

The attenuating effects of F15063 against PCP-induced social interaction deficit (a) were antagonized by the 5-HT_1A receptor antagonist WAY100,635 (b). See legend of Figure 1 for details. Rats were given saline (a) or WAY100,635 (0.63 mg kg⁻¹, s.c.) (b), 90 min before the observation period. ^**P<0.01, Bonferroni's post hoc test, following significant one-way ANOVA; for data in a, (F(5,38)=210.0, P<0.001; data in b, F(5,38)=188.1, P<0.001). N=7 pairs of rats per group.

Figure 3

Reduction by F15063 of a deficit of choice accuracy induced by chronic treatment with PCP in the RLT in rats. Each symbol represents the mean (±s.e.m.) percentage of correct responses (i.e. responses on the appropriate lever) obtained during the three sessions immediately preceding the start of the pharmacological treatment (BASAL), the 4th day of treatment (D4) and during the 5th to 14th day of treatment (D5–D14). Basal values (lefthand cluster of points) did not differ between groups of rats (one-way ANOVA: F(3,36)=1.2, P>0.05 and F (3,39)=1.9, P>0.05, for 0.04 and 0.16 mg kg⁻¹ of F15063, respectively). ^*P<0.05, ^**P<0.01, compared with vehicle–vehicle value at D4, for the corresponding treatment, Bonferroni's post hoc tests following significant one-way ANOVA (F(3,32)=18.5, P<0.001 and F(3,33)=18.6, P<0.001, for 0.04 and 0.16 mg kg⁻¹ of F15063, respectively). N=5–9 rats per group. Inset: each bar represents the average (±s.e.m.) percentage of correct responses collated across the 5th to the 14th day. ^*P<0.05, ^**P<0.01, compared with vehicle/PCP treated rats, Dunnett's post hoc test following significant one-way ANOVA. The order of treatments is the same as that in the legend on the left.

Figure 4

Reduction by F15063 of the increase in the latency time to the first response induced by chronic treatment with PCP in the RLT in rats. Each symbol represents the mean (±s.e.m.) latency time to the first response on any lever, obtained during the three sessions immediately preceding the start of the pharmacological treatment (BASAL), the 4th day of treatment (D4) and during the 5th to 14th day of treatment. Basal values did not differ between groups (one-way ANOVAs: F (3,36)=1.0, P>0.05 and F (3,39)=0.5, P>0.05, for 0.04 and 0.16 mg kg⁻¹ of F15063, respectively) For day 4, ^*P<0.05, ^**P<0.01, compared with vehicle/vehicle value at D4, for the corresponding treatment, Bonferroni's post hoc tests following significant one-way ANOVA (F (3,27)=7.1, P<0.001 and F (3,31)=5.7, P<0.05, for 0.04 and 0.16 mg kg⁻¹ of F15063, respectively). N=5–9 rats per group. Inset: each bar represents the average (±s.e.m.) latency time collated across the 5th to the 14^th day. At the lower dose, F15063 did not reverse PCP-induced effects (Dunnett's post hoc test, following significant one-way ANOVA: F(3,36)=18.6, P<0.0001). At the higher dose (0.16 mg kg⁻¹), ^**P<0.01, compared to vehicle/PCP-treated rats, Dunnett's post hoc test following significant one-way ANOVA (F (3,36)=10.9, P<0.0001). The order of treatments is the same as that in the legend on the left.

Figure 5

(a) F15063 reversed the decrease of retention score induced by scopolamine. (b) This reversal is antagonized by the dopamine D4 receptor antagonist L745,870. Each bar represents the mean (±s.e.m.). difference in the time spent in social interaction during the second encounter (T2) minus the time spent in social interaction during the first encounter (T1). (a) Vehicle or F15063 were administered i.p. to the adult rat 45 min before testing, and scopolamine (Sco: 0.63 mg kg⁻¹, s.c.) or vehicle were administered 30 min before the observation session. Scopolamine caused a reduction of the score (significant one-way ANOVA: F(5,112)=6.84, P<0.001) which was totally reversed by F15063. N=9 adult rats per dose. (b) L745,870 or vehicle were administered i.p. 15 min before vehicle or F15063. The D4 antagonist prevented the effects of F15063 against scopolamine induced amnesia N=11 adult rats per dose. For both panels: ^*P<0.05, ^**P<0.01, compared with the scopolamine-injected group; ^#P<0.05, ^##P<0.01, compared with the vehicle-injected group using Bonferroni's test, following significant ANOVA (one-way, F(5,58)=4.62, P<0.001).

Scheme 1

Synopsis of training schedules and pharmacological treatment phase for the RLT experiment.