Altered voltage-gated calcium channels in rat inferior colliculus neurons contribute to alcohol withdrawal seizures.
We have previously reported that enhanced susceptibility to alcohol withdrawal seizures (AWS) parallels the enhancement of the current density of high-threshold voltage-gated Ca(2+) (CaV) channels in rat inferior colliculus (IC) neurons. However, whether this increased current density is a cause or consequence of AWS is unclear. Here, I report changes in the current density of CaV channels in IC neurons during the course of alcohol withdrawal and the potential anticonvulsant effect of intra-IC infusions of L- and P-type CaV channel antagonists. Whole-cell currents were activated by depolarizing pulses using barium as the charge carrier. Currents and seizure susceptibility were evaluated in control animals 3h after alcohol intoxication, as well as 3h (before AWS), 24h (when AWS susceptibility is maximal), and 48h (when AWS susceptibility is no longer present) after alcohol withdrawal. Nifedipine, nimodipine (L-type antagonists) or ω-agatoxin TK (P-type antagonist) were infused intra-IC to probe the role of CaV channels in the pathogenesis of AWS. CaV current density and conductance in IC neurons were significantly increased 3 and 24h after alcohol withdrawal compared with the control group or the group tested 3h following ethanol intoxication. Blockade of L-type CaV channels within the IC completely suppressed AWS, and inhibition of P-type channels reduced AWS severity. These findings suggest that the enhancement of CaV currents in IC neurons occurs prior to AWS onset and that alterations in L- and P-type CaV channels in these neurons may underlie the pathogenesis of AWS.
Department of Pediatrics, Georgetown, University Medical Center, Washington, DC, USA. Electronic address: pn@georgetown.edu.
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D020270:Alcohol Withdrawal Seizures / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000097:blood / Q000633:toxicity; D004195:Disease Models, Animal; D000431:Ethanol / Q000097:blood / Q000633:toxicity; D007245:Inferior Colliculi / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002492:Central Nervous System Depressants; D000431:Ethanol
Calcium channels; Current density; Generalized tonic–clonic seizures; Nifedipine; Nimodipine; ω-Agatoxin TK