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Pregnenolone sulfate (PregS), an endogenous neurosteroid, which negatively and positively modulates gamma amino butyric acid subunit A (GABAA) and N-methyl D-aspartate (NMDA) receptors (R) respectively, among other potential neuroplastic changes on synaptic processes, has shown some beneficial effects on treating cognitive impairment associated with schizophrenia (CIAS) and negative symptoms. Lurasidone (Lur), an atypical antipsychotic drug (AAPD), and tandospirone (Tan), a 5-HT1AR partial agonist, have also been reported to improve cognitive or negative symptoms, or both, in some schizophrenia patients.We tested whether PregS, by itself, and in combination with Lur or Tan could rescue persistent deficits produced by subchronic treatment with the NMDAR antagonist, phencyclidine (PCP)-in episodic memory, executive functioning, and social behavior, using novel object recognition (NOR), operant reversal learning (ORL), and social interaction (SI) tasks, in male C57BL/6J mice.PregS (10, but not 3mg/kg) significantly rescued subchronic PCP-induced NOR and SI deficits. Co-administration of sub-effective doses (SEDs) of PregS (3mg/kg) + Lur (0.1mg/kg) or Tan (0.03mg/kg) rescued scPCP-induced NOR and SI deficits. Further, PregS (30, but not 10mg/kg) rescued PCP-induced ORL deficit, as did the combination of SED PregS (10mg/kg) +SED Lur (1mg/kg) or Tan (1mg/kg).PregS was effective alone and as adjunctive treatment for treating two types of cognitive impairments and negative symptoms in this schizophrenia model. Further study of the mechanisms by which PregS alone and in combination with AAPDs and 5-HT1AR partial agonists, rescues the deficits in cognition and SI in this preclinical model is indicated.PregS restored sc phencyclidine (PCP)-induced deficits in episodic memory, executive functioning, and social behavior.Sub-effective dose (SED) of PregS, plus lurasidone, or tandospirone, reversed these scPCP-induced deficits.Positive and negative modulation of NMDA and GABAARs, possibly by enhanced release of DA and ACh could attribute to PregS efficacy.