AUTHOR=Torrisi Sebastiano Alfio , Salomone Salvatore , Geraci Federica , Caraci Filippo , Bucolo Claudio , Drago Filippo , Leggio Gian Marco 

TITLE=Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00710

DOI=10.3389/fphar.2017.00710

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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, <italic>de novo</italic> drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT<sub>1A</sub> receptor (5-HT<sub>1A</sub>R) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D<sub>3</sub> (D<sub>3</sub>R) and D<sub>4</sub> receptor (D<sub>4</sub>R) antagonist activity. Multiple lines of evidence point to D<sub>3</sub>R 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 D<sub>3</sub>R antagonist, may have antipsychotic-like activity.</p><p><bold>Materials and Methods:</bold> 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 D<sub>3</sub>R-null mutant mice (D<sub>3</sub>R<sup>-/-</sup>).</p><p><bold>Results:</bold> Buspirone (3 mg⋅kg<sup>-1</sup>, 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<sup>-1</sup>, i.p.) in WT mice. Conversely, in D<sub>3</sub>R<sup>-/-</sup> mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion.</p><p><bold>Conclusion:</bold> 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 D<sub>3</sub>R 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.</p>