Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats.
BACKGROUND
Cocaine administration in rats increases locomotor activity as a result of underlying changes in neurotransmitter dynamics and intracellular signaling. The serine/ threonine phosphatase, calcineurin, is known to modulate several signaling proteins that can influence behavioral responses to cocaine.


OBJECTIVE
This study aimed to determine whether calcineurin plays a role in locomotor responses associated with acute and repeated cocaine exposure. Second, we examined cocaine-mediated changes in intracellular signaling to identify potential mechanism underlying the ability of calcineurin to influence cocaine-mediated behavior.


METHODS
Locomotor activity was assessed over 17 days in male Sprague-Dawley rats (n = 48) that received daily administration of cocaine (15 mg/kg, s.c.) or saline in the presence or absence of the calcineurin inhibitor, cyclosporine (15 mg/kg, i.p.). Non-cocaine-treated animals from this initial experiment (n = 24) also received an acute cocaine challenge on day 18 of testing.


RESULTS
Daily cyclosporine administration potentiated the locomotor response to repeated cocaine 5 min after cocaine injection and attenuated the sustained locomotor response 15 to 40 min after cocaine. Furthermore, cyclosporine pretreatment for 17 days augmented the acute locomotor response to acute cocaine 5 to 30 min after cocaine injection. Finally, repeated exposure to either cocaine or cyclosporine for 22 days increased synapsin I phosphorylation at the calcineurin-sensitive Ser 62/67 site, demonstrating a common downstream target for both calcineurin and cocaine.


CONCLUSIONS
Our results suggest that calcineurin inhibition augments locomotor responses to cocaine and mimics cocaine-mediated phosphorylation of synapsin I.
Addy
Nii A
NA
Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, 06508, USA.
Bahi
Amine
A
Taylor
Jane R
JR
Picciotto
Marina R
MR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019703:Calcineurin / Q000187:drug effects*; D065095:Calcineurin Inhibitors; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D016704:Synapsins / Q000187:drug effects; D013997:Time Factors
D065095:Calcineurin Inhibitors; D016704:Synapsins; D016572:Cyclosporine; D019703:Calcineurin; D003042:Cocaine