Cholinergic modulation of periaqueductal grey neurons: does it contribute to epileptogenesis after organophosphorus nerve agent intoxication?
Previous work has shown that a single focal microinjection of the unselective cholinergic agonist, carbachol, into the periaqueductal grey (PAG) of the midbrain is sufficient to induce forebrain seizures in rats. In order to determine the cholinergic mechanisms underlying epileptogenesis at the cellular and network level of the PAG, we performed whole-cell recordings from rat PAG neurons in vitro and examined how the activation of muscarinic and nicotinic receptors modulates cellular excitability and synaptic responses. Stimulation of muscarinic receptors produced either a pirenzepine-sensitive depolarization (40% of PAG neurons), or a gallamine-sensitive hyperpolarization (20%), suggesting the involvement of M1 and M2 receptors, respectively. In the remaining neurons (40%), no change was observed. Voltage-clamp recordings showed that muscarinic depolarization resulted from the inhibition of a resting K(+) current, in part accompanied by simultaneous activation of a presumed non-selective cation current. Muscarinic hyperpolarization was caused by the activation of a G protein-coupled, inwardly rectifying K(+) current. Stimulation of muscarinic receptors enhanced the frequency of spontaneous inhibitory postsynaptic currents (IPSCs), but strongly suppressed evoked IPSCs. In addition, nicotine almost doubled the frequency of miniature IPSCs. Based on our findings and the network properties of the PAG, we advance a scenario in which excessive stimulation of cholinergic receptors would substantially contribute to generalized seizures after organophosphorus nerve agent poisoning.
Sanada
Mitsuru
M
Department of Physiology, University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany.
Zheng
Fang
F
Huth
Tobias
T
Alzheimer
Christian
C
D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D002619:Chemical Warfare Agents; D009943:Organophosphorus Compounds; D011976:Receptors, Muscarinic