Phencyclidine Disrupts Neural Coordination and Cognitive Control by Dysregulating Translation.

Autor:	Park EH; Center for Neural Science, New York University, New York, New York., Kao HY; Center for Neural Science, New York University, New York, New York., Jourdi H; Center for Neural Science, New York University, New York, New York., van Dijk MT; Center for Neural Science, New York University, New York, New York.; Graduate Program in Neuroscience and Physiology, New York University Langone Medical Center, New York, New York., Carrillo-Segura S; Center for Neural Science, New York University, New York, New York.; Graduate Program in Mechanical and Aerospace Engineering, New York University Tandon School of Engineering, New York, New York., Tunnell KW; Center for Neural Science, New York University, New York, New York., Gutierrez J; Center for Neural Science, New York University, New York, New York., Wallace EJ; Graduate Program in Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York.; Department of Physiology and Pharmacology, State University of New York, Downstate Health Sciences University, Brooklyn, New York., Troy-Regier M; Graduate Program in Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York.; Department of Physiology and Pharmacology, State University of New York, Downstate Health Sciences University, Brooklyn, New York., Radwan B; Graduate Program in Neural Science, Center for Neural Science, New York University, New York, New York., Lesburguères E; Center for Neural Science, New York University, New York, New York., Alarcon JM; Department of Pathology, State University of New York, Downstate Health Sciences University, Brooklyn, New York.; Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York., Fenton AA; Center for Neural Science, New York University, New York, New York.; Department of Physiology and Pharmacology, State University of New York, Downstate Health Sciences University, Brooklyn, New York.; Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Health Sciences University, Brooklyn, New York.; Neuroscience Institute, NYU Langone Health, New York, New York.
Jazyk:	angličtina
Zdroj:	Biological psychiatry global open science [Biol Psychiatry Glob Open Sci] 2023 May 31; Vol. 4 (1), pp. 252-263. Date of Electronic Publication: 2023 May 31 (Print Publication: 2024).
DOI:	10.1016/j.bpsgos.2023.04.009
Abstrakt:	Background: Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. Methods: The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. Results: Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis-dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented PCP-induced discoordination and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR antagonist NVP-AAM077 unbalanced translation that engages the Akt, mTOR (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. Conclusions: PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments. (© 2023 The Authors.)
Databáze:	MEDLINE
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