Comparison of the muscarinic antagonist effects of scopolamine and L-687,306

Abstract

This study aimed to use central and peripheral assays to compare the effects of the muscarinic antagonist scopolamine with those of a novel muscarinic antagonist, L-687,306 [(3R,4R)-3-(3-cyclopropyl-1,2,4,oxadiazol[5-yl]-1-azabicyclo[2.2.1]heptane. Groups of rats were trained to discriminate the stimulus effects of the muscarinic agonist, arecoline (1.0 mg/kg); concomitant measures of response rate were recorded. Separate groups were prepared with telemetery devices for recording bradycardia induced by arecoline (10 mg/kg). Methyl arecoline and arecoline were nearly equally potent in producing a brief but profound bradycardia, indicative of an equivalent effect in the heart. L-687,306 and scopolamine were both able to block this peripheral effect of arecoline. L-687,306 produced a surmountable antagonism of both the discriminative and rate-suppressing effects of arecoline. Scopolamine, however, was unable to antagonize the rate-reducing effects of arecoline in the discrimination assay. This limited the number of rats that could respond to the discriminative stimulus effects of arecoline, as well as the amount of arecoline stimulus effects they were able to report. The data suggest that L-687,306 may be a more generally effective muscarinic antagonist than scopolamine and support earlier reports that this antagonist has less direct effect on behavior.

Nicotinic aspects of the discriminative stimulus effects of arecoline

“…1, bottom, closed circles). The muscarinic antagonist, L 687 306 (Freedman et al ., 1992; Winger et al ., 2020; Johnson et al ., 2021) antagonized the discriminative stimulus effects of arecoline (Fig. 1, top, open squares) and to a lesser degree relieved the rate-suppressing effects of arecoline (Fig.…”

“…Rats were trained to report the discriminative stimulus effects of 1.0 mg/kg s.c. arecoline by responding on one lever following administration of arecoline and to respond on another lever following administration of saline. The fundamental muscarinic effects of arecoline in this assay were established initially by evaluating the effects of a muscarinic antagonist, L 687 306 (Freedman et al ., 1992; Freedman et al ., 1993; Winger et al ., 2020; Johnson et al ., 2021), as well as two nicotinic antagonists on the discriminative stimulus effects of arecoline. Subsequently, the ability of nicotine to produce an arecoline stimulus was evaluated.…”