After long-term exposure to GABAA receptor (GABAAR) modulators, neuronal L-type voltage-gated calcium channel (L-VGCC) function is up-regulated, suggesting that an interaction with L-VGCCs may also play a role in physical dependence for GABAAR modulators (e.g., benzodiazepines). Earl and Tietz studied the effects of GABAAR modulators against recombinant Cav1.2 and Cav1.3 in human embryonic kidney cells and attempted to correlate potential effects to clinically relevant concentrations. Evaluation of benzodiazepines, allopregnanolone, pentobarbital, and ethanol in this system demonstrated state-dependent block of L-VGCCs by GABAAR modulators, with preferential interaction with the inactive and open states of the channel. The differential potency of these drugs on L-VGCCs may allow them to selectively modify distinct L-VGCC subunit-mediated neuronal functions, possibly affecting spatial memory and providing a protective activity in reducing age-related neuronal degradation. Of the drugs evaluated, only pentobarbital and ethanol inhibit L-VGCCs at clinically achievable concentrations. Therefore, inhibition of L-VGCCs may contribute to the up-regulation of L-VGCC function, drug withdrawal symptoms, and physical dependence after long-term exposure to barbiturates and ethanol but not to benzodiazepines.
See article at J Pharmacol Exp Ther 2011, 337:301–311.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics