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Muscarinic receptor agonist-mediated modulation of neuronal activity in rat cerebral cortex
1Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201.
Abstract:
Multiple cortical neuronal responses were elicited by the iontophoretic application of muscarinic receptor agonists and antagonists in the rat cerebral sensorimotor cortex in vivo. (1) The muscarinic receptor agonist, oxotremorine-M induced a biphasic effect on spontaneous firing. This was evident as an early brief increase in the firing rate over the spontaneous discharge followed by secondary inhibition of spontaneous activity. The excitation could be blocked by the muscarinic receptor non-selective antagonist atropine and by both the M1 receptor antagonist pirenzepine and the M2 receptor antagonists gallamine or methoctramine. Oxotremorine-M inhibition of spontaneous activity was not affected by the M1 receptor antagonist pirenzepine, while evaluation of its sensitivity to gallamine and methoctramine was not possible since these two M2 receptor antagonists also depressed spontaneous activity, unlike pirenzepine. Of the other two muscarinic receptor agonists, oxotremorine had inconsistent and weak excitatory effects whilst McN-A-343 had only weak excitatory or inhibitory effects on spontaneous activity. (2) Oxotremorine-M, oxotremorine and McN-A-343 had a depressant action on neuronal discharges evoked by glutamate or acetylcholine. A depressant effect of oxotremorine-M was also demonstrated on the early excitation evoked by subsequent applications of oxotremorine-M itself. Of the three muscarinic receptor agonists tested, oxotremorine-M was the most potent in evoking a long-term depression of evoked discharges, lasting from several minutes (greater than 5 min) to as long as 40 min. Oxotremorine-M-induced depression of evoked responses was most sensitive to the M2 receptor antagonists, whereas oxotremorine-induced depression was more sensitive to the M1 receptor antagonist pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Muscarinic receptor agonists like oxotremorine-M affect rat brain neurons, causing excitation and inhibition. These effects are modulated by M1 and M2 receptor antagonists, influencing neuronal firing and evoked responses.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Muscarinic acetylcholine receptors play crucial roles in central nervous system function.
- Understanding receptor subtype-specific actions is key to developing targeted therapeutics.
Purpose of the Study:
- To investigate the effects of muscarinic receptor agonists and antagonists on neuronal activity in the rat sensorimotor cortex.
- To differentiate the roles of M1 and M2 muscarinic receptor subtypes in modulating cortical neuronal responses.
Main Methods:
- In vivo iontophoresis of muscarinic agonists (oxotremorine-M, oxotremorine, McN-A-343) and antagonists (atropine, pirenzepine, gallamine, methoctramine) in rat cerebral sensorimotor cortex.
- Recording of spontaneous and evoked neuronal firing rates.
Main Results:
- Oxotremorine-M induced a biphasic response: initial excitation followed by inhibition of spontaneous firing.
- Excitation by oxotremorine-M was blocked by non-selective and subtype-specific antagonists.
- All tested agonists depressed glutamate- or acetylcholine-evoked neuronal discharges, with oxotremorine-M showing potent, long-lasting depression.
- Oxotremorine-M-induced depression was sensitive to M2 antagonists, while oxotremorine-induced depression was sensitive to M1 antagonists.
Conclusions:
- Muscarinic receptor activation differentially affects spontaneous and evoked neuronal activity in the sensorimotor cortex.
- M1 and M2 receptor subtypes exhibit distinct roles in modulating cortical excitability and response potentiation.
- Findings provide insights into the complex pharmacology of muscarinic receptors in the brain.