Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice

Abdu Adem, Nather Madjid, Oliver Stiedl, Alessandra Bonito-Oliva, Åsa Konradsson-Geuken, Sarah Holst, Gilberto Fisone, Sven Ove Ögren

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR)transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA)task in mice and the ability of typical and atypical antipsychotic drugs (APDs)to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg)dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D 2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D 2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT 1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT 1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.

Original languageEnglish
Pages (from-to)616-628
Number of pages13
JournalEuropean Neuropsychopharmacology
Volume29
Issue number5
DOIs
Publication statusPublished - May 2019

Keywords

  • 5-HT receptor
  • Atypical antipsychotic drugs
  • Clozapine
  • Emotional memory
  • Passive avoidance
  • Phencyclidine

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)

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