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Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes Through Dopamine D 3 Receptor Blockade

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Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes Through Dopamine D 3 Receptor Blockade

Sebastiano Alfio Torrisi et al. Front Pharmacol.

Abstract

Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R) and D4 receptor (D4R) antagonist activity. Multiple lines of evidence point to D3R as a valid therapeutic target for the treatment of several neuropsychiatric disorders including schizophrenia. In the present study, we tested the hypothesis that buspirone, behaving as dopamine D3R antagonist, may have antipsychotic-like activity. Materials and Methods: Effects of acute administration of buspirone was assessed on a wide-range of schizophrenia-relevant abnormalities induced by a single administration of the non-competitive NMDAR antagonist MK-801, in both wild-type mice (WT) and D3R-null mutant mice (D3R-/-). Results: Buspirone (3 mg⋅kg-1, i.p.) was devoid of cataleptogenic activity in itself, but resulted effective in counteracting disruption of prepulse inhibition (PPI), hyperlocomotion and deficit of temporal order recognition memory (TOR) induced by MK-801 (0.1 mg⋅kg-1, i.p.) in WT mice. Conversely, in D3R-/- mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion. Conclusion: Taken together, these results indicate, for the first time, that buspirone, might be a potential therapeutic medication for the treatment of schizophrenia. In particular, buspirone, through its D3R antagonist activity, may be a useful tool for improving the treatment of cognitive deficits in schizophrenia that still represents an unmet need of this disease.

Keywords: MK-801; antipsychotics; buspirone; dopamine D3 receptor; prepulse inhibition; schizophrenia; temporal order recognition.

Figures

FIGURE 1
FIGURE 1
Buspirone counteracted MK-801-induced TOR memory impairment in WT mice. (A) Cartoon illustrating the TOR test and the schedule of treatment. Buspirone (Bus, 3 mg⋅kg-1, i.p.) or vehicle (Veh), clozapine (Clo, 1 mg⋅kg-1, i.p.) or Veh and MK-801 (0.1 mg⋅kg-1, i.p.) or Veh were injected 45, 30, and 20 min respectively, before the sample phase 2. (B,C) Discrimination ratio (DR) displayed by Veh + Veh (n = 10), Veh + MK-801 (n = 10), Bus + MK-801 (n = 9), Clo + MK-801 (n = 9), Bus + Veh (n = 8), Clo + Veh (n = 5) WT mice during the test phase. Data are shown as mean ± SEM. DR [(less recently experienced object exploration time - more recently experienced object exploration time)/total exploration time]. ∗∗∗p < 0.001 vs. Veh + Veh WT mice; ††p < 0.01 and p < 0.05 vs. Veh + MK-801 WT mice (One-way ANOVA and Newman–Keuls post hoc test).
FIGURE 2
FIGURE 2
Buspirone blocked MK-801-stimulated hyperlocomotion, but did not cause catalepsy in WT mice. Buspirone (Bus, 3 mg⋅kg-1, i.p.) or vehicle (Veh), clozapine (Clo, 1 mg⋅kg-1, i.p.) or Veh and MK-801 (0.1 mg⋅kg-1, i.p.) or Veh were injected 45 min, 30 min and 20 min respectively, before the open field. (A,B) Locomotor activity (crossings) at each 5-min time point displayed by Veh + Veh (n = 11), Veh + MK-801 (n = 11), Bus + MK-801 (n = 10), Clo + MK-801 (n = 10), Bus + Veh (n = 9), Clo + Veh (n = 9) WT mice. (C,D) Locomotor activity (crossings) over a 30-min test period displayed by the same mice. (E) Duration of catalepsy state 30, 60, 90, and 120 min after drug injection (n = 6 animals/group). Haloperidol (Hal, 1 mg⋅kg-1) was used as positive control. Data are shown as mean ± SEM. ∗∗∗p < 0.001, ∗∗p < 0.01 vs. Veh + Veh WT mice; †††p < 0.001 and p < 0.05 vs. Veh + MK-801 WT mice; ∗∗∗p < 0.001 vs. Veh (Two-way repeated-measures ANOVA and Newman–Keuls post hoc test).
FIGURE 3
FIGURE 3
Buspirone blocked MK-801-induced PPI disruption in WT mice. Buspirone (Bus, 3 mg⋅kg-1, i.p.) or vehicle (Veh), clozapine (Clo, 1 mg⋅kg-1, i.p.) or Veh and MK-801 (0.1 mg⋅kg-1, i.p.) or Veh were injected 45, 30, and 20 min before the PPI test, respectively. (A,B) Animal movements displayed by Veh + Veh (n = 10), Veh + MK-801 (n = 10), Bus + MK-801 (n = 9), Clo + MK-801 (n = 8), Bus + Veh (n = 13), Clo + Veh (n = 8) WT mice. (C,D) PPI% displayed by the same WT mice. Data are shown as mean ± SEM. ∗∗p < 0.01,p < 0.05 vs. Veh + Veh WT mice; p < 0.05 vs. Veh + MK-801 WT mice; (Two-way ANOVA with or without repeated-measures and Newman–Keuls post hoc test).
FIGURE 4
FIGURE 4
Buspirone was ineffective in preventing MK-801-induced TOR memory deficit and hyperlocomotion. Buspirone (Bus, 3 mg⋅kg-1, i.p.) or vehicle (Veh) and MK-801 (0.1 mg⋅kg-1, i.p.) or Veh were injected 45 min, and 20 min respectively, before the sample phase 2 or the open field test. (A,B) Discrimination ratio (DR) displayed by Veh + Veh (n = 5), Veh + MK-801 (n = 6), Bus + MK-801 (n = 5), Bus + Veh (n = 6), D3R-/- mice during the test phase. DR [(less recently experienced object exploration time - more recently experienced object exploration time)/total exploration time]. (C,D) Locomotor activity (crossings) at each 5-min time point displayed by Veh + Veh (n = 11), Veh + MK-801 (n = 11), Bus + MK-801 (n = 11), Bus + Veh (n = 6), D3R-/- mice. (E,F) Locomotor activity (crossings) over a 30-min test period displayed by the same mice. Data are shown as mean ± SEM. ∗∗∗p < 0.001, ∗∗p < 0.01, p < 0.05 vs. Veh + Veh D3R-/- mice; †††p < 0.001, ††p < 0.01 and p < 0.05 vs. Veh + MK-801 WT mice; (One-way or two-way repeated-measures ANOVA and Newman–Keuls post hoc test).

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