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The Journal of Neuroscience, November 5, 2003, 23(31):10093-10099

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Cellular/Molecular
Neuroprotection by Nicotine in Mouse Primary Cortical Cultures Involves Activation of Calcineurin and L-Type Calcium Channel Inactivation

Tanya R. Stevens,¹ Stefan R. Krueger,² Reiko M. Fitzsimonds,² and Marina R. Picciotto¹

Departments of ¹Psychiatry and ²Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06508

Regulation of intracellular calcium influences neuronal excitability, synaptic plasticity, gene expression, and neurotoxicity. In this study, we investigated the role of calcium in mechanisms underlying nicotine-mediated neuroprotection from glutamate excitotoxicity. Neuroprotection by nicotine in primary cortical cultures was not seen in knock-out mice lacking the 2 subunit of the nicotinic acetylcholine receptor (nAChR). Neuroprotection was partially blocked in wild-type cultures by -bungarotoxin, an antagonist of the 7 nAChR subtype, suggesting a potential cooperative role for these subtypes. Pretreatment with nicotine decreased glutamate-mediated calcium influx in primary cortical cultures by 41%, an effect that was absent in cultures from knock-out mice lacking the 2 subunit of the nAChR. This effect was dependent on calcium entry through L-type channels during nicotine pretreatment in wild-type cultures. The ability of nicotine to decrease glutamate-mediated calcium influx was occluded by cotreatment with nifedipine during glutamate application, suggesting that nicotine pretreatment decreased subsequent activity of L-type calcium channels. Treatment with the calcineurin antagonists FK506 and cyclosporine during pretreatment eliminated both nicotine-mediated neuroprotection and the effects of nicotine on L-type channels. We conclude that neuroprotective effects of nicotine in cortical neurons involve both 2- and 7-containing nAChRs, activation of calcineurin, and decreased intracellular calcium via L-type channels.

Key words: calcium imaging; cell death; glutamate; FK506; nifedipine; nicotinic acetylcholine receptors

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Received June 26, 2003; revised September 11, 2003; accepted September 12, 2003.

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