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Effects of T-type calcium channel blockers on cocaine-induced hyperlocomotion and thalamocortical GABAergic abnormalities in mice

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Abstract

Rationale

Repetitive cocaine exposure has been shown to induce GABAergic thalamic alterations. Given the key role of T-type (CaV3) calcium channels in thalamocortical physiology, the direct involvement of these calcium channels in cocaine-mediated effects needs to be further explored.

Objective

The objective of this study was to investigate the effect of T-type calcium channel blockers on acute and repetitive cocaine administration that mediates thalamocortical alterations in mice using three different T-type blockers: 2-octanol, nickel, and mibefradil.

Methods

During in vitro experiments, whole-cell patch-clamp recordings were conducted in ventrobasal (VB) thalamic neurons from mice treated with acute repetitive cocaine administration (3 × 15 mg/kg, i.p., 1 h apart), under bath application of mibefradil (10 μM), 2-octanol (50 μM), or nickel (200 μM). After systemic administration of T-type calcium channel blockers, we evaluated locomotor activity and also recorded GABAergic neurotransmission onto VB neurons in vitro.

Results

Bath-applied mibefradil, 2-octanol, or nickel significantly reduced both GABAergic neurotransmission and T-type currents of VB neurons in cocaine-treated mice. In vivo i.p. pre-administration of either mibefradil (20 mg/kg and 5 mg/kg) or 2-octanol (0.5 mg/kg and 0.07 mg/kg) significantly reduced GABAergic mini frequencies onto VB neurons. Moreover, both mibefradil and 2-octanol were able to decrease cocaine-induced hyperlocomotion.

Conclusion

The results shown in this study strongly suggest that T-type calcium channels play a key role in cocaine-mediated GABAergic thalamocortical alterations, and further propose T-type channel blockers as potential targets for future pharmacological strategies aimed at treating cocaine’s deleterious effects on physiology and behavior.

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Acknowledgments

The authors would like to thank Maria Eugenia Martin and Paula Felman for their excellent technical and administrative assistance, Dr. Carina Weissmann for proofreading our manuscripts, and Dr. Joaquin Piriz for his critical reading of our work. Dr. Bisagno has been authorized to study drug-abuse substances in animal models by the National Board of Medicine Food and Medical Technology, Ministerio de Salud, Argentina (A.N.M.A.T). This work was supported by grants from: FONCyT, Agencia Nacional de Promoción Científica y Tecnológica; BID 1728 OC.AR. PICT 2007-1009, PICT 2008-2019 and PIDRI-PRH 2007 (to Dr. Urbano), Wellcome Trust, grant # 068941/Z/02/Z; ANCyT; grant # 6220; UBACYT; grant # X171, and X223; FONCyT, Agencia Nacional de Promoción Científica y Tecnológica; BID 1728 OC.AR. PICT2005 #32,113 and #13,367; and BID 1728 OC.AR. PICT 2006 # 199 (to Dr. Uchitel), National Institutes of Health NS13742 (to Dr. Llinás) and PICT 31953 (ANPCyT) and UBACYT M073 (to Dr. Wikinski).

The experiments included in this work comply with the current laws of Argentina. Authors have full control of all primary data and agree to allow the journal to review their data, if requested.

Conflict of interest

Authors also report no conflict of interest, financial or otherwise, related directly or indirectly to this work.

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Authors and Affiliations

  1. Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Junín 956, piso 5, C1113, Buenos Aires, Argentina

    Verónica Bisagno, Mariana Raineri, Viviana Peskin & Silvia I. Wikinski

  2. Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Ciudad Universitaria, Intendente Guiraldes 2670, pabellón 2, piso 2, C1428BGA, Buenos Aires, Argentina

    Osvaldo D. Uchitel & Francisco J. Urbano

  3. Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue, 10016, New York, NY, USA

    Rodolfo R. Llinás

Authors
  1. Verónica Bisagno
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  2. Mariana Raineri
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  3. Viviana Peskin
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  4. Silvia I. Wikinski
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  5. Osvaldo D. Uchitel
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  6. Rodolfo R. Llinás
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  7. Francisco J. Urbano
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Corresponding authors

Correspondence to Rodolfo R. Llinás or Francisco J. Urbano.

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Bisagno, V., Raineri, M., Peskin, V. et al. Effects of T-type calcium channel blockers on cocaine-induced hyperlocomotion and thalamocortical GABAergic abnormalities in mice. Psychopharmacology 212, 205–214 (2010). https://doi.org/10.1007/s00213-010-1947-z

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  • DOI: https://doi.org/10.1007/s00213-010-1947-z

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