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The Journal of Neuroscience, April 2, 2008, 28(14):3769-3780; doi:10.1523/JNEUROSCI.5251-07.2008

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Behavioral/Systems/Cognitive
Glutamatergic Contributions to Nicotinic Acetylcholine Receptor Agonist-Evoked Cholinergic Transients in the Prefrontal Cortex

Vinay Parikh,¹ Kingson Man,¹ Michael W. Decker,² and Martin Sarter¹

¹Department of Psychology, University of Michigan, Ann Arbor, Michigan 48109-1043, and ²Neuroscience Research, Abbott Laboratories, Abbott Park, Illinois 60064-6125

Correspondence should be addressed to Martin Sarter, Department of Psychology, University of Michigan, 530 Church Street, 4032 East Hall, Ann Arbor, MI 48109-1043. Email: msarter{at}umich.edu

Because modulation of cortical cholinergic neurotransmission has been hypothesized to represent a necessary mechanism mediating the beneficial cognitive effects of nicotine and nicotinic acetylcholine receptor (nAChR) subtype-selective agonists, we used choline-sensitive microelectrodes for the real-time measurement of ACh release in vivo, to characterize cholinergic transients evoked by nicotine and the 4β2*-selective nAChR partial agonist 2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride (ABT-089), a clinically effective cognition enhancer. In terms of cholinergic signal amplitudes, ABT-089 was significantly more potent than nicotine in evoking ACh cholinergic transients. Moreover, cholinergic signals evoked by ABT-089 were characterized by faster signal rise time and decay rate. The nAChR antagonist mecamylamine attenuated the cholinergic signals evoked by either compound. Cholinergic signals evoked by ABT-089 were more efficaciously attenuated by the relatively β2*-selective nAChR antagonist dihydro-β-erythroidine. The 7 antagonist methyllycaconitine did not affect choline signal amplitudes but partly attenuated the relatively slow decay rate of nicotine-evoked cholinergic signals. Furthermore, the AMPA receptor antagonist DNQX as well as the NMDA receptor antagonist APV more potently attenuated cholinergic signals evoked by ABT-089. Using glutamate-sensitive microelectrodes to measure glutamatergic transients, ABT-089 was more potent than nicotine in evoking glutamate release. Glutamatergic signals were highly sensitive to tetrodotoxin-induced blockade of voltage-regulated sodium channels. Together, the present evidence indicates that compared with nicotine, ABT-089 evokes more potent and sharper cholinergic transients in prefrontal cortex. Glutamatergic mechanisms necessarily mediate the cholinergic effects of nAChR agonists in the prefrontal cortex.

Key words: nicotine; acetylcholine; ABT-089; glutamate; choline/glutamate-sensitive microelectrodes; cognition

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Received Nov. 27, 2007; revised Jan. 11, 2008; accepted Feb. 26, 2008.

Correspondence should be addressed to Martin Sarter, Department of Psychology, University of Michigan, 530 Church Street, 4032 East Hall, Ann Arbor, MI 48109-1043. Email: msarter{at}umich.edu

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