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Published on: October 12, 2017
GABAergic systems modulate nicotinic receptor-mediated seizures in mice
Peter Dobelis1, Scott Hutton, Ying Lu
1Department of Pharmacology, University of ColoradoHealth Science Center, Denver, CO, USA.
Summary
Nicotinic receptor agonists and antagonists can induce seizures in mice, with effects linked to GABAergic systems. This study models nicotinic receptor-mediated seizures via GABAergic pathways.
Area of Science:
- Neuropharmacology
- Neuroscience
Background:
- Nicotinic acetylcholine receptors (nAChRs) play a role in various physiological processes, including neuronal excitability.
- The precise mechanisms underlying nAChR-mediated seizures are not fully understood.
- Investigating the relationship between nAChRs and inhibitory neurotransmission is crucial for understanding seizure disorders.
Purpose of the Study:
- To investigate the pharmacology of nicotinic receptor-mediated seizures in C3H mice.
- To explore the potential involvement of GABAergic systems in these seizures.
- To compare the sensitivity of different inbred mouse strains to various seizure-inducing agents.
Main Methods:
- Administration of eleven nicotinic agonists and six antagonists centrally (i.c.v.) in C3H mice.
- Assessment of seizure induction and blockade by specific nAChR agonists and antagonists.
- Evaluation of correlations between seizure potency and effects on GABA release and receptor desensitization.
- Comparison of inbred mouse strain sensitivity to nicotine, picrotoxin, bicuculline, and kainate.
Main Results:
- Epibatidine and epiboxidine were potent nicotinic agonists for seizure induction; acetylcholine and GTS-21 were least potent.
- Nicotine-induced seizures were blocked by mecamylamine and methyllycaconitine but not dihydro-beta-erythroidine.
- All tested antagonists induced seizures at high doses, with d-tubocurarine being most potent.
- A correlation was found between agonist seizure potency and inhibition of nicotine-stimulated GABA release via receptor desensitization.
- Nicotine-induced seizures strongly correlated with picrotoxin- and bicuculline-induced seizures (GABAA antagonists), but not kainate-induced seizures.
Conclusions:
- Nicotinic receptor-mediated seizures are influenced by GABAergic systems.
- A model is proposed where nicotinic receptor activation leads to seizures through modulation of GABAergic neurotransmission.
- Specific nAChR subtypes and GABAergic pathways are implicated in the development of seizures.
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