THE EFFECTS OF BRUCINE AND ALCURONIUM ON THE INHIBITION OF [H-3]ACETYLCHOLINE RELEASE FROM RAT STRIATUM BY MUSCARINIC RECEPTOR AGONISTS

1 Radioligand binding experiments indicate that the affinity of muscar inic receptors for their agonists may be enhanced by allosteric modula tors. We have now investigated if brucine can enhance the inhibitory e ffects of muscarinic receptor agonists on the electrically evoked rele ase of [H-3]acetylcholine ([H-3]ACh) from superfused slices of rat str iatum. 2 The evoked release of [H-3]ACh was inhibited by all agonists tested (i.e., furmethide, oxotremorine-M, bethanechol and oxotremorine ). 3 Brucine enhanced the inhibitory effects of furmethide, oxotremori ne-M and bethanechol on the evoked [H-3]ACh release without altering t he inhibitory effect of oxotremorine. 4 Alcuronium was applied for com parison and found to diminish the inhibitory effect of furmethide on t he evoked [H-3]ACh release. 5 The results demonstrate that it is possi ble both to enhance and diminish the functional effects of muscarinic receptor agonists by allosteric modulators. 6 The direction of the obs erved effects of brucine and alcuronium on [H-3]ACh release fully agre es with the effects of these modulators on the affinities of human M-4 receptors for furmethide, oxotremorine-M, bethanechol and oxotremorin e, as described by Jakubik et al. (1997). This supports the view that the presynaptic muscarinic receptors responsible for the autoinhibitio n of ACh release in rat striatum belong to the M-4 muscarinic receptor subtype.