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The Journal of Neuroscience, August 8, 2007, 27(32):8571-8580; doi:10.1523/JNEUROSCI.2601-07.2007

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Behavioral/Systems/Cognitive
Role of Calcineurin in Nicotine-Mediated Locomotor Sensitization

Nii A. Addy,1,2 Eugenio F. Fornasiero,2 Tanya R. Stevens,2 Jane R. Taylor,1,2 and Marina R. Picciotto1,2

1Interdepartmental Neuroscience Program and 2Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508

Correspondence should be addressed to Dr. Marina R. Picciotto, 34 Park Street, 3rd Floor Research, New Haven, CT 06508. Email: marina.picciotto{at}yale.edu

Calcineurin is a serine/threonine phosphatase that contributes to the effects of nicotine on calcium signaling in cultured cortical neurons; however, the role of calcineurin in behavioral responses to nicotine in vivo has not been examined. We therefore determined whether calcineurin blockade could alter nicotine-mediated locomotor sensitization in Sprague Dawley rats using systemic or brain region-specific administration of the calcineurin inhibitors cyclosporine or FK506. Systemic cyclosporine administration decreased calcineurin activity in the brain, attenuated nicotine-mediated locomotor sensitization, and blocked the effects of nicotine on DARPP32 (dopamine- and cAMP-regulated phosphoprotein-32) activation in the striatum. Direct infusion of calcineurin inhibitors cyclosporine or FK506 into the ventral tegmental area (VTA) also attenuated nicotine-mediated locomotor sensitization, whereas infusion of rapamycin, which binds to FK-binding protein but does not inhibit calcineurin, did not affect sensitization. Together, the data suggest that activation of calcineurin, particularly in the VTA, is a novel signaling event important for nicotine-mediated behavior and intracellular signaling.

Key words: nicotine; calcineurin; locomotor activity; sensitization; ventral tegmental area; DARPP32

Received March 5, 2007; revised June 29, 2007; accepted June 29, 2007.

Correspondence should be addressed to Dr. Marina R. Picciotto, 34 Park Street, 3rd Floor Research, New Haven, CT 06508. Email: marina.picciotto{at}yale.edu






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