Distinct muscarinic receptors inhibit release of gamma-aminobutyric acid and excitatory amino acids in mammalian brain.

Abstract

Intracellular recordings were made from neurons of rat lateral amygdala, nucleus accumbens, and striatum in vitro. Synaptic potentials mediated by Y-aminobutyric acid and by excitatory amino acids were isolated pharmacologically by using receptor antagonists, and their amplitudes were used as a measure oftransmitter release. Mucanrne and acetylcholine inhibited the release of both y-aminobutyric acid and excitatory amino acids, but measurements of the dissociation equilibrium constants for the antagonists piren- ,4]benzodiazepine-6-one, methoctramine, and hexahydrosiladifenidol indicated clearly that different muscarinic receptors were involved (MI and probably M3, respectively). The differential localization of distinct muscarinc receptor subtypes on terminals releasing the major inhibitory and excitatory transmitters of the brain could be exploited therapeutically in some movement disorders and Alzheimer disease.Acetylcholine (AcCho) has diverse functional roles in the mammalian brain, including actions at muscarinic receptors that are important for memory (1). Cholinergic neurons are lost in Alzheimer disease, and one therapeutic approach has been to develop drugs that mimic the neurotransmitter action of missing AcCho (1). However, such drugs, like AcCho itself, will have different effects at different muscarinic receptors in the brain, and not all of these effects may be desired. Three muscarinic receptors (M1-M3) can be distinguished pharmacologically, but five (ml-mS) have been identified by molecular cloning (ml-m3 correspond to M1-M3) (2-8).Fibers containing 'y-aminobutyric acid (GABA) and excitatory amino acids such as glutamate provide synaptic inputs to virtually all central neurons; therefore, in addition to their direct effects on neurons (9, 10), muscarinic agonists will also excite or inhibit cells by acting presynaptically to change release of these neurotransmitters. In the present experiments, the release of GABA and excitatory amino acids (glutamate) was assayed by recording the amplitude of depolarizing synaptic potentials from neurons in three brain regions where AcCho is known to play an important functional role-the amygdala, nucleus accumbens, and striatum. METHODSAdult rats were anesthetized with halothane and killed by a heavy blow to the chest. The brain was rapidly removed, and a block of tissue containing nucleus accumbens, dorsal striatum, or amygdaloid complex was sectioned with a Vibratome. Intracellular recordings were made from slices (300 ,am thick) by using electrodes containing 2 M KCI (11-13).The superfusing solution was a bicarbonate buffer gassed with 95% 02/5% CO2 and contained 2.5 mM KCI, 2.4 mM CaC12, 1.3 mM MgCl2, 1.2 mM NaH2PO4, 26 mM NaHCO3, 126 mM NaCi, and 10 mM glucose. The slice was completely submerged in this flowing solution, which was prewarmed to 370C. Drugs were applied by changing this solution to one that contained the drug. A bipolar tungsten-in-glass stimulating electrode was used for focal stimulation. The components of the synaptic potential...

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

“…Amygdalar neurons via muscarinic mediation have been associated with bursting phenomena (Yajeya et al, 1997), postsynaptically (Washburn and Moises, 1992) and presynaptically (Sugita et al, 1991). Bursting activity was further tied to a complement of presynaptic muscarinic receptors that were estimated to be comprised of 50% M 3 , 30% M 2 , and 20% or less M 1 , but most likely not due to the well characterized M-current (Yajeya et al, 1997).…”

The Role of Acetylcholine in Cocaine Addiction

“…ACh also directly influences glutaminergic and GABAergic effects on midbrain DA neurons, further effecting striatal DA release (Grillner et al, 2000). High concentrations of mGlu2 receptors on striatal cholinergic neurons (Pisani et al, 2002), mediated through M 2 and M 3 receptors, reduce striatal glutaminergic release (Sugita et al, 1991). Serotonergic fibers from the raphe nucleus also demonstrate a potent excitatory effect on striatal cholinergic interneurons (Bonsi et al, 2007).…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…We recently discovered a novel epigenetic pathway whereby H3K9me3-dependent heterochromatin condensation leads to transcriptional deregulation of muscarinic acetylcholine (Ach) receptor 1 (CHRM1) by occupying its promoter in HD striatal cells [69]. CHRM1 promotes phosphatidylinositol hydrolysis and intracellular Ca 2+ mobilization, while CHRM2 is coupled negatively to adenylate-cyclase activity [72][73][74][75]. The conventional wisdom is that loss of cholinergic receptor function directly results in synaptic dysfunction through inadequate intracellular signal transductions in neurons.…”

“…The conventional wisdom is that loss of cholinergic receptor function directly results in synaptic dysfunction through inadequate intracellular signal transductions in neurons. The CHRM1 is highly expressed in the striatum of control brain, but is downregulated in HD striatum [72,76,77]. Despite the deregulation of striatal cholinergic system has been suggested in the pathophysiology of HD, the cellular mechanisms underlying the epigenetic regulation of CHRM1 expression in striatal neurons are unknown.…”