Role of calcineurin in nicotine-mediated locomotor sensitization.
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.
Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Nii A
NA
Addy
Eugenio F
EF
Fornasiero
Tanya R
TR
Stevens
Jane R
JR
Taylor
Marina R
MR
Picciotto
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D009538:Nicotine / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000201:enzymology / Q000502:physiology
D065095:Calcineurin Inhibitors; D009538:Nicotine; D016572:Cyclosporine; D019703:Calcineurin