Role of Calcineurin in Nicotine-Mediated Locomotor Sensitization

• Published in: The Journal of neuroscience Vol. 27; no. 32; pp. 8571 - 8580
• Main Authors: Addy, Nii A, Fornasiero, Eugenio F, Stevens, Tanya R, Taylor, Jane R, Picciotto, Marina R
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 08-08-2007; Society for Neuroscience
• Subjects: Animals; Calcineurin - physiology; Calcineurin Inhibitors; Cyclosporine - administration & dosage; Male; Motor Activity - drug effects; Motor Activity - physiology; Nicotine - administration & dosage; Rats; Rats, Sprague-Dawley; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - enzymology; Ventral Tegmental Area - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2601-07.2007

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.