Regulation of prefrontal glutamate by the endogenous neuromodulator kynurenic acid as measured by rapid electrochemistry: relevance to schizophrenia
Loading...
Date
2010-06
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
Schizophrenia is one of the most debilitating neuropsychiatric disorders, with a prevalence of approximately 1% worldwide. Symptoms include impairing deficits in cognitive processes (e.g., working memory, attention, and cognitive flexibility) which are currently elusive to treatment. Alpha-7 nicotinic acetylcholine receptors (α7 nAChRs) may be a critical link between the dysregulated cortical glutamatergic transmission and cognitive deficits in schizophrenia. Elevated levels of the endogenous, astrocyte-derived neuromodulator kynurenic acid (KYNA), a potent, non-competitive α7 nAChR antagonist, in the brains and cerebrospinal fluid (CSF) of schizophrenic patients suggests that KYNA binding may cause or exacerbate cortical dysregulation in schizophrenia. Thus, we used a state-of-the-art microelectrode array (MEA) to amperometrically examine the regulation of glutamate release by KYNA in the prefrontal cortex (PFC) of intact, freely moving rats. The MEA allows for the selective quantification of glutamate levels with second-by-second resolution (500-800 ms), a limit of detection of ≤0.5 μM, and outstanding spatial resolution (<100 μm). Intraperitoneal (i.p.) injections of L-kynurenine (25 and 50 mg/kg), KYNA’s bioprecursor, dose-dependently decreased basal glutamate levels in PFC (nadir after 50 mg/kg kynurenine: 31% decrease from baseline values). However, co-administration of galantamine (3 mg/kg), a drug that competes with KYNA at an allosteric potentiating site of the α7 nAChR, attenuated kynurenine-mediated reductions in cortical glutamate. These data in intact animals demonstrate KYNA’s α7 nAChR-mediated regulation of glutamate release in the PFC. Drugs that normalize cortical glutamatergic function by attenuating KYNA production or by countering its effects on α7 nAChRs may be effective cognition-enhancing therapeutics in schizophrenic patients.
Description
Keywords
kynurenic acid, schizophrenia, prefrontal cortex, microelectrode array