On the presence in the cerebral cortex of muscarinic receptor subtypes which differ in neuronal localization, function and pharmacological properties

The existence in rat frontal cerebral cortex of subtypes of muscarinic receptors was investigated by using as a receptor-mediated functional response the release of neurotransmitters from isolated nerve endings. Synaptosomes prelabeled with 3H]choline or 3H]dopamine were depolarized with 15 mM KCl. Acetylcholine (ACh) concentration-dependently decreased the release of 3H]ACh and increased that of 3H]dopamine. Both actions of ACh were counteracted by the classical muscarinic antagonists atropine and quinuclidinyl benzylate. The two antagonists did not discriminate between the muscarinic presynaptic receptors sited on cholinergic terminals (muscarinic autoreceptors) and those located on dopamine nerve endings (muscarinic heteroreceptors). The apparent affinity (pA2) values for the two receptors were: 8.41 and 8.57 with atropine and 8.55 and 8.34 with quinuclidinyl benzylate. However, other muscarinic antagonists behaved differently. Dicyclomine strongly antagonized ACh at the heteroreceptors (pA2 = 8.69), whereas it was ineffective at the autoreceptors when tested at 5 microM. Pirenzepine had a similar behavior, although its affinity at the heteroreceptors was lower (pA2 = 6.33). In contrast, secoverine antagonized ACh at the autoreceptors with an affinity (pA2 = 7.58) higher than that showed at the heteroreceptors (pA2 = 6.51). The data support the existence in the frontal cortex of muscarinic receptors that are located on different neurons, mediate different functional responses and are pharmacologically distinguishable.