Abstract
It has been proposed that activation of nicotinic acetylcholine receptors (nAChRs) can activate the prefrontal cortex, enhancing attention and cognition. Nicotine can stimulate the release of several different neurotransmitters in many brain regions. In the present study, we found that stimulation of nAChRs by nicotine or the endogenous agonist, acetylcholine (ACh), induces a large spontaneous increase in glutamate release onto layer V pyramidal neurons of the prefrontal cortex. This release of glutamate, measured by spontaneous excitatory postsynaptic currents (sEPSCs) in the prefrontal cortical slice, depends on intact thalamocortical terminals. It can be suppressed by μ-opioids or eliminated by blocking action potentials. The increase in sEPSCs is sensitive to low concentrations of nicotine, suggesting the involvement of high-affinity (eg α4β2) nAChRs. Recent work has shown alterations in prefrontal α4β2 nAChRs in autism and schizophrenia, two conditions that are distinguished by abnormal prefrontal cortical activation as well as difficulty in certain aspects of cognition and integrating social and emotional cues. We show that mice lacking the β2 nAChR subunit do not show increased sEPSCs with either nicotine or ACh, again implicating high-affinity nicotinic receptors. These findings give new insight into the mechanism by which nicotine affects excitatory neurotransmission to the output neurons of the cerebral cortex in a pathway that is critical for cognitive function and reward expectation.
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Acknowledgements
We thank Dr Leonard Kaczmarek and Dr Patricia Goldman-Rakic for valuable discussions and insights. Ms Nancy Margiotta contributed excellent technical assistance. This study was funded by NIMH (GA) and a Scottish Rite fellowship (EKL).
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Lambe, E., Picciotto, M. & Aghajanian, G. Nicotine Induces Glutamate Release from Thalamocortical Terminals in Prefrontal Cortex. Neuropsychopharmacol 28, 216–225 (2003). https://doi.org/10.1038/sj.npp.1300032
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DOI: https://doi.org/10.1038/sj.npp.1300032
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