Effects of metabotropic glutamate receptor 2/3 agonism and antagonism on schizophrenia-like cognitive deficits induced by phencyclidine in rats.

Abstract

Dysregulation of glutamate neurotransmission may play a role in cognitive deficits in schizophrenia. Manipulation of glutamate signaling using drugs acting at metabotropic glutamate receptors has been suggested as a novel approach to treating schizophrenia-related cognitive dysfunction. We examined how the metabotropic glutamate receptor 2/3 agonist LY379268 and the metabotropic glutamate receptor 2/3 antagonist LY341495 altered phencyclidine-induced disruptions in performance in the 5-choice serial reaction time task. This test assesses multiple cognitive modalities characteristically impaired in schizophrenia that are disrupted by phencyclidine administration. Acute LY379268 alone did not affect 5-choice serial reaction time task performance, except for nonspecific response suppression at high doses. Acute LY379268 administration exacerbated phencyclidine-induced disruption of attentional performance in this task, while acute LY341495 did not alter 5-choice serial reaction time task performance during phencyclidine exposure. Chronic LY341495 impaired attentional performance in the 5-choice serial reaction time task by itself, but attenuated phencyclidine-induced excessive timeout responding. The mixed effects of metabotropic glutamate receptor 2/3 agonism and antagonism on cognitive performance under baseline conditions and after disruption with phencyclidine demonstrate that different aspects of cognition may respond differently to a given pharmacological manipulation, indicating that potential antipsychotic or pro-cognitive medications need to be tested for their effects on a range of cognitive modalities. Our findings also suggest that additional mechanisms, besides cortical glutamatergic transmission, may be involved in certain cognitive dysfunctions in schizophrenia.

• Authors: Nurith Amitai, Athina Markou
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 639 Issue 1-3 Pg. 67-80 (Aug 10 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20371228 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier B.V. All rights reserved.

Chemical References

• Amino Acids
• Antipsychotic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Excitatory Amino Acid Agents
• LY 341495
• LY 379268
• Receptors, Metabotropic Glutamate
• Xanthenes
• metabotropic glutamate receptor 2
• metabotropic glutamate receptor 3
• Phencyclidine

Topics

• Amino Acids (pharmacology, therapeutic use)
• Animals
• Antipsychotic Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology, therapeutic use)
• Cognition (drug effects, physiology)
• Excitatory Amino Acid Agents (classification, pharmacology, therapeutic use)
• Male
• Phencyclidine (administration & dosage, pharmacology)
• Rats
• Rats, Wistar
• Receptors, Metabotropic Glutamate (agonists, antagonists & inhibitors, metabolism)
• Schizophrenia (chemically induced, metabolism)
• Time Factors
• Xanthenes (pharmacology, therapeutic use)