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.
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This work was supported by USPHS grants RO1 MH083729 (JB & RS) and P50 MH103222 (RS; Conte Center for Translational Research).
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Animal care and experimentation was performed in accordance with protocols approved by The Ohio State University Institutional Laboratory Animal Care and Use Committee and was consistent with the NIH Guide for the Care and Use of Laboratory Animals.
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Phenis, D., Vunck, S.A., Valentini, V. et al. Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task. Psychopharmacology 237, 1723–1735 (2020). https://doi.org/10.1007/s00213-020-05495-y
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DOI: https://doi.org/10.1007/s00213-020-05495-y