Discriminative stimulus properties of the muscarinic receptor agonists Lu 26-046 and O-Me-THPO in rats: evidence for involvement of different muscarinic receptor subtypes

The discriminative cues induced by the muscarinic receptor agonists Lu 26-046 ((-)-7-methyl-3(2-propynyloxy)-4,5,6,7-tetrahydroisothiazolo [4,5-c]pyridine ) and O-Me-THPO (3-methoxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine) were investigated. The results were compared with those obtained for the binding profiles of these agonists at central muscarinic receptors and with results concerning their functional effects at peripheral muscarinic receptors in vitro. Lu 26-046 had preferential affinity for M1 versus M2 receptors (Ki index [3H]quinuclidinyl benzilate ([3H]QNB/[3H]pirenzepine 4.2) and had partial agonistic activity at M1 and M2 receptors in rat superior cervical ganglion and guinea pig left atrim, respectively. A weak antagonistic effect at M3 receptors in guinea pig ileum was observed. O-Me-THPO had non-selective agonistic effects at peripheral M1, M2 and M3 receptors and had a slight preference for central M2 receptors in binding experiments (M2/M1 index 0.31). Lu 26-046 dose dependently substituted for Lu 26-046 and partially substituted for O-Me-THPO in rats trained to discriminate Lu 26-046 and O-Me-THPO from saline, respectively. The (+)-enantiomer of Lu 26-046, Lu 26-047, had weak partial M1 agonistic activity and M2/M3 antagonistic effects at peripheral receptors. Lu 26-047 also had a high M2/M1 index (9.3) in binding experiments. Lu 26-047 substituted for Lu 26-046, but preferentially inhibited the effect of O-Me-THPO. Pilocarpine had a preferential effect in Lu 26-046-trained rats, while oxotremorine and arecoline had preferential effects in O-Me-THPO-trained rats. Large increases in latency times or a disruption of responding was generally observed. These compounds were full agonists at peripheral M1, M2 and M3 receptors. The muscarinic receptor antagonist scopolamine antagonized the effect of O-Me-THPO and partially inhibited the effect of Lu 26-046. Scopolamine partially substituted for Lu 26-046. The quaternary muscarinic receptor agonist N-methyl atropine had no effect, indicating that the cues are mediated by central muscarinic receptors. It is suggested that the discriminative cues of Lu 26-046 and O-Me-THPO are preferentially mediated by central M1 (partial) and M2 receptor stimulation, respectively. The role of central M3 receptors is not known.