Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

Psychopharmacology (Berl). 2008 Sep;200(1):129-39. doi: 10.1007/s00213-008-1189-5. Epub 2008 Jun 28.

Abstract

Rationale: 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.

Conclusion: Our results suggest that calcineurin inhibition augments locomotor responses to cocaine and mimics cocaine-mediated phosphorylation of synapsin I.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Calcineurin / drug effects*
  • Calcineurin Inhibitors
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Cyclosporine / pharmacology
  • Male
  • Motor Activity / drug effects*
  • Phosphorylation / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Synapsins / drug effects
  • Time Factors

Substances

  • Calcineurin Inhibitors
  • Synapsins
  • Cyclosporine
  • Calcineurin
  • Cocaine