Background: The septo-hippocampal cholinergic pathway has been implicated in epileptogenesis, and genetic factors influence the response to cholinergic agents, but limited data are available on cholinergic involvement in alcohol withdrawal severity. Thus, the relationship between cholinergic activity and responsiveness and alcohol withdrawal was investigated in a genetic animal model of ethanol withdrawal severity.
Methods: Cholinergic convulsant sensitivity was examined in alcohol-naïve Withdrawal Seizure-Prone (WSP) and-Resistant (WSR) mice. Animals were administered nicotine, carbachol, or neostigmine via timed tail vein infusion, and the latencies to onset of tremor and clonus were recorded and converted to threshold dose. We also used microdialysis to measure basal and potassium-stimulated acetylcholine (ACh) release in the CA1 region of the hippocampus. Potassium was applied by reverse dialysis twice, separated by 75 min. Hippocampal ACh also was measured during testing for handling-induced convulsions.
Results: Sensitivity to several convulsion endpoints induced by nicotine, carbachol, and neostigmine were significantly greater in WSR versus WSP mice. In microdialysis experiments, the lines did not differ in basal release of ACh, and 50 mM KCl increased ACh output in both lines of mice. However, the increase in release of ACh produced by the first application of KCl was 2-fold higher in WSP versus WSR mice. When hippocampal ACh was measured during testing for handling-induced convulsions, extracellular ACh was significantly elevated (192%) in WSP mice, but was nonsignificantly elevated (59%) in WSR mice.
Conclusions: These results suggest that differences in cholinergic activity and postsynaptic sensitivity to cholinergic convulsants may be associated with ethanol withdrawal severity and implicate cholinergic mechanisms in alcohol withdrawal. Specifically, WSP mice may have lower sensitivity to cholinergic convulsants compared with WSR because of postsynaptic receptor desensitization brought on by higher activity of cholinergic neurons.