Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone a 5-HT1A Partial Agonist

摘要

Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)2A/dopamine D2 antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT1A partial agonist properties, tandospirone, a selective 5-HT1A partial agonist, haloperidol, a D2 antagonist, and pimavanserin, a 5-HT2A inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1–7), followed by a 7-day washout (day8–14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT1A antagonists, further evidence for the importance of 5-HT1A receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.