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

Psychopharmacology (Berl). 2010 Oct;212(2):205-14. doi: 10.1007/s00213-010-1947-z. Epub 2010 Jul 21.

Abstract

Rationale: Repetitive cocaine exposure has been shown to induce GABAergic thalamic alterations. Given the key role of T-type (Ca(V)3) 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 x 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, T-Type / drug effects*
  • Calcium Channels, T-Type / metabolism
  • Cocaine / administration & dosage
  • Cocaine / toxicity*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Locomotion / drug effects
  • Male
  • Mibefradil / administration & dosage
  • Mibefradil / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Nickel / administration & dosage
  • Nickel / pharmacology
  • Octanols / administration & dosage
  • Octanols / pharmacology
  • Patch-Clamp Techniques
  • Thalamus / drug effects
  • Thalamus / metabolism
  • gamma-Aminobutyric Acid / drug effects*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Octanols
  • Mibefradil
  • gamma-Aminobutyric Acid
  • 2-octanol
  • Nickel
  • Cocaine