Blockade of cholinergic neurotransmission by muscarinic receptor antagonists produces profound deficits in attention and memory. However, the antagonists used in previous studies bind to more than one of the five muscarinic receptor subtypes. Here we examined memory in mice with a null mutation of the gene coding the M1 receptor, the most densely distributed muscarinic receptor in the hippocampus and forebrain. In contrast with previous studies using nonselective pharmacological antagonists, the M1 receptor deletion produced a selective phenotype that included both enhancements and deficits in memory. Long-term potentiation (LTP) in response to theta burst stimulation in the hippocampus was also reduced in mutant mice. M1 null mutant mice showed normal or enhanced memory for tasks that involved matching-to-sample problems, but they were severely impaired in non-matching-to-sample working memory as well as consolidation. Our results suggest that the M1 receptor is specifically involved in memory processes for which the cortex and hippocampus interact.

https://olegsenkov.com/downloads/Anagnostaras_Nature,_2002.pdf

Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice.

https://www.cell.com/neuron/pdf/S0896-6273(06)00073-0.pdf

M1 Receptors Play a Central Role in Modulating AD-like Pathology in Transgenic Mice

http://www.samento.com.ec/sciencelib/sarticles/Pteropodine81B1.pdf

Pteropodine and isopteropodine positively modulate the function of rat muscarinic M1 and 5-HT2 receptors expressed in Xenopus oocyte

It is well known, although not well understood, that smoking and eating just do not go together. Smoking is associated with decreased food intake and lower body weight. Nicotine, administered either by smoking or by smokeless routes, is considered the major appetite-suppressing component of tobacco. Perhaps the most renowned example of nicotine's influence on appetite and feeding behavior is the significant weight gain associated with smoking cessation. This article presents an overview of the literature at, or near, the interface of nicotinic receptors and appetite regulation. We first consider some of the possible sites of nicotine's action along the complex network of neural and non-neural regulators of feeding. We then present the hypothesis that the lateral hypothalamus is a particularly important locus of the anorectic effects of nicotine. Finally, we discuss the potential role of endogenous cholinergic systems in motivational feeding, focusing on cholinergic pathways in the lateral hypothalamus.

/pdf/nicotinic-receptor-mediated-effects-on-appetite-and-food-4da0frdnzy.pdf

Nicotinic receptor-mediated effects on appetite and food intake.

The M5 muscarinic receptor is the most recent member of the muscarinic acetylcholine receptor family (M1-M5) to be cloned. At present, the physiological relevance of this receptor subtype remains unknown, primarily because of its low expression levels and the lack of M5 receptor-selective ligands. To circumvent these difficulties, we used gene targeting technology to generate M5 receptor-deficient mice (M5R−/− mice). M5R−/− mice did not differ from their wild-type littermates in various behavioral and pharmacologic tests. However, in vitro neurotransmitter release experiments showed that M5 receptors play a role in facilitating muscarinic agonist-induced dopamine release in the striatum. Because M5 receptor mRNA has been detected in several blood vessels, we also investigated whether the lack of M5 receptors led to changes in vascular tone by using several in vivo and in vitro vascular preparations. Strikingly, acetylcholine, a powerful dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5R−/− mice. This effect was specific for cerebral blood vessels, because acetylcholine-mediated dilation of extra-cerebral arteries remained fully intact in M5R−/− mice. Our findings provide direct evidence that M5 muscarinic receptors are physiologically relevant. Because it has been suggested that impaired cholinergic dilation of cerebral blood vessels may play a role in the pathophysiology of Alzheimer's disease and focal cerebral ischemia, cerebrovascular M5 receptors may represent an attractive therapeutic target.

https://www.pnas.org/content/pnas/98/24/14096.full.pdf

Cholinergic dilation of cerebral blood vessels is abolished in M 5 muscarinic acetylcholine receptor knockout mice

Five muscarinic receptor genes (m1-m5) that encode distinct muscarinic receptor subtypes have been cloned. Because of their structural homology and pharmacological similarity, ligand binding probes currently available do not clearly distinguish among the subtypes. To obtain a clear distribution within the CNS of molecularly defined muscarinic receptor subtypes, seven brain regions were examined for the expression of the respective mRNAs. The most sensitive method for detecting mRNA is through amplification of the respective cDNAs. Brain regions were obtained from male Wistar rats, and total RNA was isolated. The isolates were extensively treated with RNase-free DNase to remove any residual genomic DNA. Total RNA (1 microgram) was reverse-transcribed using random primers and reverse transcriptase. The resulting cDNA was amplified using a thermal cycler, and the polymerase chain reaction (PCR)-amplified products were analyzed by gel electrophoresis containing ethidium bromide and visualized with fluorescent illumination. PCR-amplified samples were also injected directly onto an HPLC anion exchange column and quantified by UV detection. Each of the five muscarinic subtypes was found in every brain region examined. The m1 subtype was most abundant in cortex and gradually declined in content caudally to the spinal cord. The m2 subtype was most abundant in thalamus-hypothalamus and ponsmedulla. The m4 subtype was found in greatest amount in the striatum, whereas m3 and m5 were expressed consistently throughout the CNS. The combination of RT-PCR and HPLC provides a rapid and sensitive method for quantifying the expression of mRNA coding for all five muscarinic receptor subtypes derived from the CNS.

Jian Wei

Papers

m1-m5 muscarinic receptor distribution in rat CNS by RT-PCR and HPLC.