title: Effects of T-type calcium channel blockers on cocaine-induced hyperlocomotion and thalamocortical GABAergic abnormalities in mice.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Instituto de Investigaciones Farmacológicas ININFA-UBA-CONICET, Junín 956, Piso 5, C1113, Buenos Aires, Argentina.
authors.forename: Verónica
authors.initials: V
authors.lastname: Bisagno
authors.forename: Mariana
authors.initials: M
authors.lastname: Raineri
authors.forename: Viviana
authors.initials: V
authors.lastname: Peskin
authors.forename: Silvia I
authors.initials: SI
authors.lastname: Wikinski
authors.forename: Osvaldo D
authors.initials: OD
authors.lastname: Uchitel
authors.forename: Rodolfo R
authors.initials: RR
authors.lastname: Llinás
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Urbano
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008124:Locomotion / Q000187:drug effects; D008297:Male; D020748:Mibefradil / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009532:Nickel / Q000008:administration & dosage / Q000494:pharmacology; D000442:Octanols / Q000008:administration & dosage / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D000442:Octanols; D020748:Mibefradil; D005680:gamma-Aminobutyric Acid; C067943:2-octanol; D009532:Nickel; D003042:Cocaine