Psychopharmacology

, Volume 200, Issue 1, pp 129–139

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

  • Nii A. Addy
  • Amine Bahi
  • Jane R. Taylor
  • Marina R. Picciotto
Original Investigation
  • 96 Downloads

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.

Keywords

Cocaine Calcineurin Synapsin Locomotor activity Sensitization Nucleus accumbens 

Supplementary material

213_2008_1189_Fig1_ESM.gif (202 kb)
Supplementary Figure 1

Repeated cyclosporine administration inhibits locomotor responses after repeated administration of 10 mg/kg cocaine. a Schematic representation of the locomotor testing paradigm in male Sprague–Dawley rats (n = 21). b Chronic cyclosporine administration did not alter habituation activity in the 30 min before cocaine administration. c Daily cocaine administration (10 mg/kg, s.c.) led to a sensitized and sustained locomotor response (main effect of cocaine, p < 0.001) while coadministration of cyclosporine gave a trend towards attenuation of the sustained locomotor response to cocaine (cocaine × cyclosporine interaction, p < 0.07). d Repeated cyclosporine administration (15 mg/kg, i.p.) attenuated the sustained response to repeated cocaine (p < 0.05, independent sample t test) after several time bins in the 60-min session on test days 11, 13, 15, and 17. All data are displayed as the mean ± SEM (GIF 201 KB)

213_2008_1189_Fig1_ESM.tif (1.3 mb)
High resolution image file (TIFF 1.31 MB)
213_2008_1189_Fig2_ESM.gif (50 kb)
Supplementary Figure 2

Chronic cyclosporine increases the locomotor response to acute administration of 10 mg/kg cocaine. a Cyclosporine pretreatment for 17 days gave a trend towards a potentiated increase in total locomotor activity to an acute 10 mg/kg cocaine challenge on day 18 (p = 0.09, independent sample t test). b Analysis of locomotor activity in 5-min bins to the acute 10 mg/kg cocaine challenge on day 18 (GIF 50 KB).

213_2008_1189_Fig2_ESM.tif (493 kb)
Supplementary Figure 2High resolution image file (TIFF 492 KB).
213_2008_1189_Fig3_ESM.gif (43 kb)
Supplementary Figure 3

Stereoyptic counts after repeated cocaine and cyclosporine administration. a Stereotypic movements increased over the 17 day testing periods in (main effect of test day, p < 0.001). However, cyclosporine coadministration in the 15 mg/kg cocaine study did not alter the stereotypic activity associated with 15 mg/kg cocaine administration. b Stereotypic movements also increased over the testing period in the 10 mg/kg cocaine study (main effect of test day, p < 0.001). In addition, coadministration of cyclosporine gave a trend towards attenuation of the stereotypic activity associated with repeated administration of 10 mg/kg cocaine (p < 0.07, cocaine × cyclosporine interaction) (GIF 43 KB)

213_2008_1189_Fig3_ESM.tif (431 kb)
High resolution image file (TIFF 430 KB)
213_2008_1189_Fig4_ESM.gif (53 kb)
Supplementary Figure 4

Repeated cyclosporine administration results in decreased weight gain. Animals that received cyclosporine (either alone or in combination with cocaine) showed a main effect of cyclosporine administration over testing day in both the 15-mg/kg cocaine study (p < 0.001, 4A) and the 10-mg/kg cocaine study (p < 0.001, 4B) (GIF 53 KB).

213_2008_1189_Fig4_ESM.tif (748 kb)
High resolution image file (TIFF 748 KB).

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Nii A. Addy
    • 1
    • 2
  • Amine Bahi
    • 2
  • Jane R. Taylor
    • 1
    • 2
  • Marina R. Picciotto
    • 1
    • 2
    • 3
  1. 1.Interdepartmental Neuroscience ProgramYale University School of MedicineNew HavenUSA
  2. 2.Department of PsychiatryYale University School of MedicineNew HavenUSA
  3. 3.New HavenUSA

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