Second-by-Second Analysis of Alpha 7 Nicotine Receptor Regulation of Glutamate Release in the Prefrontal Cortex of Awake Rats

These experiments utilized an enzyme-based microelectrode selective for the second-by-second detection of extracellular glutamate to reveal the alpha 7-based nicotinic modulation of glutamate release in the prefrontal cortex (PFC) of freely moving rats. Rats received intracortical infusions of the nonselective nicotinic agonist nicotine (12.0 mM, 1.0 mu g/0.4 mu l) or the selective alpha 7 agonist choline (2.0 mM/0 4 mu l). The selectivity of drug-induced glutamate release was assessed in subgroups of animals pretreated with the alpha 7 antagonist, alpha-bungarotoxin (alpha-BGT, 10 mu M), or kynurenine (10 mu M) the precursor of the astrocyte-derived, negative allosteric alpha 7 modulator kynurenic acid. Local administration of nicotine increased glutamate signals (maximum amplitude = 4.3 +/- 0.6 mu M) that were cleared to baseline levels in 493 +/- 80 seconds Pretreatment with alpha-BGT or kynurenine attenuated nicotine-induced glutamate by 61% and 60%, respectively. Local administration of choline also increased glutamate signals (maximum amplitude = 6 3 +/- 0.9 mu M). In contrast to nicotine-evoked glutamate release, choline-evoked signals were cleared more quickly (28 +/- 6 seconds) and pretreatment with alpha-BGT or kynurenine completely blocked the stimulated glutamate release. Using a method that reveals the temporal dynamics of in vivo glutamate release and clearance, these data indicate a nicotinic modulation of cortical glutamate release that is both alpha 7- and non-alpha 7-mediated Furthermore, these data may also provide a mechanism underlying the recent focus on alpha 7 full and partial agonists as therapeutic agents in the treatment of cortically mediated cognitive deficits in schizophrenia. Synapse 63:1069-1082, 2009. (C) 2009 Wiley-Liss, Inc