Second-by-second measurement of nicotine-evoked glutamate release in the prefrontal cortex : Relevance to schizophrenia

Abstract

Alpha-₇nicotinic acetylcholine receptors (α₇nAChR) have been suggested as a critical link between dysregulated cortical glutamatergic transmission and cognitive deficits seen in schizophrenia. We used a state-of-the-art microelectrode array (MEA) to amperometrically determine the effects of α₇nAChR ligands on glutamatergic transmission in the prefrontal cortex of intact, freely moving rats. The MEA allows quantification of glutamate release and clearance with second-to-second resolution, an L.O.D. of ~0.25 μM, with high selectivity against oxidants and an outstanding spatial resolution (i.e. < 20 μm). Rats received intra-cortical infusions of nicotine (1.0 μg/0.4 μL) or choline (2.0 mM/0.4 μL).  The selectivity of drug-induced glutamate release was assessed in subgroups of animals pre-treated with the α-bungarotoxin (α-BGT, 10 μM) or kynurenine (10 μM) the precursor of the astrocyte-derived, negative allosteric α₇nAChR modulator kynurenic acid.  Local infusions of nicotine increased glutamate signals (maximum amplitude = 4.3 ± 0.6 μM).  Pre-treatment with α-BGT or kynurenine attenuated nicotine-induced glutamate by 61% and 60%, respectively.  Choline also increased glutamate signals (maximum amplitude = 6.3 ± 0.9 μM).  In contrast to nicotine-evoked glutamate release, choline-evoked signals were cleared more quickly and pre-treatment with α-BGT or kynurenine completely blocked the stimulated glutamate release. These data in intact animals give us a basis to examine nicotinic modulation of cortical glutamate release that is both α₇– and non-α₇-mediated in various animal models of schizophrenia currently studied in our laboratory. We postulate drugs that normalize cortical glutamatergic and cholinergic transmission in these animal models are likely to be effective cognition-enhancing antipsychotics.