David Phenis1,2, Sarah A Vunck1, Valentina Valentini3, Hugo Arias4, Robert Schwarcz5, John P Bruno6,7. 1. Department of Psychology, The Ohio State University, Columbus, OH, USA. 2. Department of Neuroscience, The Ohio State University, Columbus, OH, USA. 3. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. 4. Department of Pharmacology and Physiology, College of Osteopathic Medicine, Oklahoma State University Center for Health Sciences, Tahlequah, OK, USA. 5. Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA. 6. Department of Psychology, The Ohio State University, Columbus, OH, USA. Bruno.1@osu.edu. 7. Department of Neuroscience, The Ohio State University, Columbus, OH, USA. Bruno.1@osu.edu.
Abstract
RATIONALE: Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor. OBJECTIVES: The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). METHODS: DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. RESULTS: Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals. CONCLUSIONS: These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.
RATIONALE: Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor. OBJECTIVES: The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). METHODS:DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. RESULTS: Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals. CONCLUSIONS: These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.
Entities:
Keywords:
4-Cl-kynurenic acid; D-cycloserine; Delayed non-matching to position task; Galantamine; Kynurenic acid; PAM-2; Working memory
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