Arecoline Desensitizes Carbachol‐Stimulated Phosphatidylinositol Breakdown in Rat Brain Cortices

Abstract

To understand the effects of arecoline administration on the muscarinic cholinergic signaling pathway, rats were injected with arecoline, 10 mg/kg i.p., and the carbachol‐stimulated phosphoinositide breakdown in rat brain cortical slices was examined. In vivo administration of arecoline resulted in inhibition of carbachol‐stimulated phosphoinositide turnover in rat brain cortical slices. Arecoline was a partial agonist with peak effects of 30% of the maximum as obtained with carbachol. Coaddition of arecoline inhibited the carbachol‐stimulated phosphoinositide breakdown. Pretreatment of rat brain cortical slices with arecoline in vitro resulted in a dose‐dependent inhibition of carbachol‐stimulated [3H]inositol monophosphate accumulation. The inhibition occurred rapidly, with half‐maximal inhibition occurring at 15 min and maximal inhibition achieved within 60 min. The inhibition of phosphoinositide breakdown was recovered 1 h after arecoline was removed. When synaptoneurosomes were used for the ligand binding studies, arecoline pretreatment was found to have decreased the maximal ligand binding (Bmax) without inducing any marked change in binding affinity (KD). The influence could be recovered by incubating the synaptoneurosomes in the absence of arecoline for 2 h. Taken together, these data suggest that the underlying mechanism by which phosphoinositide turnover is inhibited is arecoline‐induced receptor sequestration.

Arecoline inhibits catecholamine release from perfused rat adrenal gland1

“…Effect of arecoline on CA secretion evoked by ACh, excess K + , DMPP and McN-A-343 from the perfused rat adrenal glands After perfusion with oxygenated Krebs bicarbonate solution for 1 h, basal CA release from the isolated perfused rat adrenal glands amounted to 23.1±2.2 ng per 2 min (n=6). Because the addition of arecoline in rat brain cortical slices inhibited the carbach ol-stimulated phosphoinositide breakdown [15] , we initially attempted to examine the effects of arecoline itself on CA secretion from the perfused model of the rat adrenal glands. However, in the present study, arecoline (1×10 -4 -1×10 -3 mol/L) by itself did not produce any effect on basal CA output of the perfused rat adrenal glands (data not shown).…”

“…However, arecoline appears to be a full agonist in membranes prepared from rat cortical slices regardless of guanosine 5'-O-(3-thiotriphosphate) concentrations [14] . To assess the influence of arecoline treatment on muscarinic receptor-associated phosphoinositide signaling pathways, Lee and colleagues [15] investigated the effects of acute and chronic administration of arecoline on muscarinic cholinergic receptor-stimulated phosphoinositide turnover in rat brain cortical slices. They found that administration of arecoline inhibited carbachol-stimulated phosphoinositide turnover.…”

“…However, arecoline appears to be a full agonist in membranes prepared from rat cortical slices, regardless of guanosine 5'-O-(3-thiotriphosphate) concentrations [14] . Recently, it has been suggested that the underlying mechanism by which phosphoinositide turnover is inhibited in rat cortical slices is arecoline-induced receptor sequestration [15] . Yang and colleagues reported that arecoline exerted its excitatory action by binding M 2 -muscarinic receptors on the cell membrane of neurons of the locus coeruleus [16] .…”