Effects of T-type calcium channel blockers on cocaine-induced hyperlocomotion and thalamocortical GABAergic abnormalities in mice.
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.
Bisagno
Verónica
V
Instituto de Investigaciones Farmacológicas ININFA-UBA-CONICET, Junín 956, Piso 5, C1113, Buenos Aires, Argentina.
Raineri
Mariana
M
Peskin
Viviana
V
Wikinski
Silvia I
SI
Uchitel
Osvaldo D
OD
Llinás
Rodolfo R
RR
Urbano
Francisco J
FJ
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
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D000442:Octanols; D020748:Mibefradil; D005680:gamma-Aminobutyric Acid; C067943:2-octanol; D009532:Nickel; D003042:Cocaine