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The effects of intrahippocampal injections to the M1-selective antagonist pirenzepine and the M2-selective antagonist AF-DX 116 were examined on performance of a representational memory task in rats. Although both antagonists impaired performance, pirenzepine was more potent than AF-DX 116. Pirenzepine (70.8 +/- 2.8% correct) produced a greater deficit than AF-DX 116 (83.3 +/- 0.0%) at 70 micrograms, and the deficit at 10 micrograms (83.3 +/- 2.8%) was equal to that produced by 70 micrograms of AF-DX 116. The data provide additional support for the cholinergic hypothesis of memory and new information regarding the subtypes of muscarinic receptors likely to be involved in representational memory. Based on the greater susceptibility of representational memory to the effects of pirenzepine, it is suggested that M1 receptors in the hippocampus play a greater role in memory function than M2 receptors.

Subtype selective agonists and antagonists were used to examine the pharmacology of the low-Km GTPase response in the rat cortex. The M2-selective agonist oxotremorine, which is a weak partial agonist for M1 receptors in the brain, stimulated low Km GTPase activity with an EC50 value of 1.0 microM. Oxotremorine was nearly a full agonist and demonstrated no partial agonist activity in the presence of optimal concentrations of the agonists carbachol or oxotremorine-M, which stimulate all muscarinic responses. These data suggest that the GTPase response is associated with M2 receptors. Pirenzepine (M1-selective) and AF-DX 116 (M2-selective) inhibited oxotremorine-stimulated GTPase activities in cortex with IC50 values of 4.0 and 2.2 microM, respectively. Since pirenzepine is substantially more potent than AF-DX 116 for binding muscarinic receptors in the cortex (Messer et al., J. Med. Chem., 32 (1989) 1164), M2 receptors contribute more to the GTPase response than M1 receptors.

Recent evidence has suggested that gallamine may act as an antagonist on presynaptic M2 muscarinic receptors which regulate acetylcholine release. The possibility that gallamine may potentiate learning by enhancing the release of acetylcholine was examined using a behavioral paradigm known to depend on cholinergic activity. Rats were cannulated bilaterally for intrahippocampal (i.h.) injections and adapted to a T-maze before the series of injections was initiated. The effects of bilateral i.h. injections of saline or gallamine (10 micrograms total) were examined on the learning of a win-stay, paired-run task in a T-maze. During the first few sessions, both saline- and gallamine-treated animals achieved below 50% correct responses. Both groups of animals gradually improved performance on the task although, contrary to expectations, gallamine-treated animals did not learn as rapidly as saline-injected animals. To verify the deleterious effects of gallamine on learning, the experiment was repeated using a second group of rats. Similar results were observed; gallamine-treated animals learned to perform the task at a slower rate than the saline-injected controls. The results suggest that treatment strategies with cholinomimetics may impair, rather than enhance performance after long-term administrations.