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

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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.

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Acknowledgements

This work was supported by DA14241 and DA11717. NAA was supported by MH18882 (American Psychological Association) and DA021459. AB was supported by Fellowship for advanced researchers from the Swiss National Science Foundation (PA00A-117453). MRP was supported by DA00436.

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Authors and Affiliations

  1. Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, 06508, USA

    Nii A. Addy, Jane R. Taylor & Marina R. Picciotto

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06508, USA

    Nii A. Addy, Amine Bahi, Jane R. Taylor & Marina R. Picciotto

  3. 34 Park Street, 3rd Floor Research, New Haven, CT, 06508, USA

    Marina R. Picciotto

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  1. Nii A. Addy
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  2. Amine Bahi
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Correspondence to Marina R. Picciotto.

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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)

High resolution image file (TIFF 1.31 MB)

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).

Supplementary Figure 2

High resolution image file (TIFF 492 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)

High resolution image file (TIFF 430 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).

High resolution image file (TIFF 748 KB).

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Addy, N.A., Bahi, A., Taylor, J.R. et al. Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats. Psychopharmacology 200, 129–139 (2008). https://doi.org/10.1007/s00213-008-1189-5

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  • DOI: https://doi.org/10.1007/s00213-008-1189-5

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