GABAA receptors containing α6 subunits (α6GABAARs) in the cerebellum have -been implicated in
schizophrenia. It was reported that the
GABA synthesizing
enzymes were downregulated whereas α6GABAARs were upregulated in postmortem cerebellar tissues of patients with
schizophrenia and in a rat model induced by chronic
phencyclidine (PCP). We have previously demonstrated that
pyrazoloquinolinone Compound 6, an α6GABAAR-highly selective positive allosteric modulator (PAM), can rescue the disrupted prepulse inhibition (PPI) induced by
methamphetamine (METH), an animal model mimicking the sensorimotor gating deficit based on the hyper-dopaminergic hypothesis of
schizophrenia. Here, we demonstrate that not only Compound 6, but also its structural analogues, LAU463 and LAU159, with similarly high α6GABAAR selectivity and their respective deuterated derivatives (DK-I-56-1, DK-I-58-1 and DK-I-59-1) can rescue METH-induced PPI disruption. Besides, Compound 6 and DK-I-56-I can also rescue the PPI disruption induced by acute administration of PCP, an animal model based on the hypo-glutamatergic hypothesis of
schizophrenia. Importantly, Compound 6 and DK-I-56-I, at doses not affecting spontaneous locomotor activity, can also rescue impairments of social interaction and novel object recognition in mice induced by chronic PCP treatments. At similar doses, Compound 6 did not induce sedation but significantly suppressed METH-induced hyperlocomotion. Thus, α6GABAAR-selective PAMs can rescue not only disrupted PPI but also hyperlocomotion, social withdrawal, and
cognitive impairment, in both METH- and PCP-induced animal models mimicking
schizophrenia, suggesting that they are a potential novel
therapy for the three core symptoms, i.e. positive symptoms, negative symptoms, and
cognitive impairment, of
schizophrenia.