zed below were obtained in collaborative studies: To examine whether the recently discovered fast depolarization-induced charge movement in the M2R is responsible for M2R-mediated control of acetylcholine release, M2R KO mice were used as a tool. Inhibition of the M2R charge movement in Xenopus oocytes correlated well with inhibition of acetylcholine release at the mouse neuromuscular junction. These results suggest that, in addition to calcium influx, charge movement in GPCRs is also necessary for transmitter release control. (Kupchik YM, et al. A novel fast mechanism for GPCR-mediated signal transduction - control of neurotransmitter release. J. Cell Biol. 192, 137-151, 2011) The involvement of M4Rs in the reinforcing effects of cocaine were examined in chronic intravenous cocaine self-administration experiments. For this analysis, wild-type and M4R KO mice were used. Behavioral studies showed that M4Rs play an important role in regulating the dopaminergic reward circuitry. Thus, central M4Rs may serve as a new target for the treatment of drug addiction. (Schmidt LS, et al. Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice. Psychopharmacology (Berl) 216, 367378, 2011) Different muscarinic receptor KO mice were used as tools to explore which muscarinic receptor subtype mediates vasodilation of small arteries. This analysis showed that M3Rs mediate cholinergic vasodilation in cutaneous, skeletal muscle, and renal interlobar arteries. These findings suggest that M3Rs may represent a novel target for the treatment of hypertension or local disturbances in blood flow. (Gericke A, et al.. Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice. Am. J. Physiol. Heart Circ. Physiol. 300, H1602- H1608, 2011) To investigate the potential role of the M4R in catalepsy induced by antipsychotics (haloperidol and risperidone) as well as the anti-cataleptic effects of the non-selective anticholinergic drug scopolamine, M4R KO mice and their wild-type littermates served as tools. Behavioral studies strongly suggested that central M4Rs play a key role in mediating the motor side effects associated with the use of antipsychotic drugs. The experimental data also supported the concept that M4Rs represent an attractive target for the pharmacological treatment of antipsychotic-induced as well as idiopathic parkinsonism. (Fink-Jensen A, et al. Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor. Eur. J. Pharmacol. 656, 39-44, 2011) Using mutant mice that lack M4Rs selectively in D1 dopamine receptor-expressing neurons (D1-M4-KO mice), we investigated the role of this neuronal population in the antipsychotic-like effects of xanomeline in amphetamine-induced hyperactivity and apomorphine-induced climbing. Interestingly, the antipsychotic-like effects of xanomeline in both models were almost completely abolished in D1-M4-KO mice, suggesting that M4Rs co-localized with D1 dopamine receptors are critically involved in mediating the antipsychotic-like effects of xanomeline. These findings support the concept that M4R agonists may prove useful for the treatment of psychosis. (Dencker D, et al. Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline. J. Neurosci. 31, 5905-5908, 2011) Studies with wild-type and M1R KO mice demonstrated that M1R dysfunction may contribute to mood disorders and that M1Rs and the downstream ERK pathway may serve as potential therapeutic targets for alleviating manic symptoms such as psychomotor hyperactivity. (Creson TK, et al. Lithium treatment attenuates muscarinic M1 receptor dysfunction. Bipolar Disord. 13, 238-249, 2011) Previous work has demonstrated that the M3R is over-expressed in colon cancer. Studies with Apc(min/+) mice lacking M3Rs showed that the absence of M3R signaling was associated with a striking reduction in colon tumor number and volume. Similar findings were obtained with scopolamine butylbromide, a non-subtype-selective muscarinic receptor antagonist. These data indicate that M3Rs play a critical role in the pathophysiology of colon cancer and that M3R antagonists may prove useful for the treatment of intestinal neoplasia. (Raufman JP, et al. Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice. Carcinogenesis, 2011, Aug 1;Epub ahead of print)

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2011
Total Cost
$341,197
Indirect Cost
City
State
Country
Zip Code
Bradley, Sophie J; Bourgognon, Julie-Myrtille; Sanger, Helen E et al. (2017) M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. J Clin Invest 127:487-499
Leaderbrand, Katherine; Chen, Helen J; Corcoran, Kevin A et al. (2016) Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory. Learn Mem 23:631-638
Mei, Feng; Lehmann-Horn, Klaus; Shen, Yun-An A et al. (2016) Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. Elife 5:
Darby, Matthew; Schnoeller, Corinna; Vira, Alykhan et al. (2015) The M3 muscarinic receptor is required for optimal adaptive immunity to helminth and bacterial infection. PLoS Pathog 11:e1004636
Shen, Weixing; Plotkin, Joshua L; Francardo, Veronica et al. (2015) M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia. Neuron 88:762-73
Shin, Jung Hoon; Adrover, Martín F; Wess, Jürgen et al. (2015) Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens. Proc Natl Acad Sci U S A 112:8124-9
Kistemaker, Loes E M; van Os, Ronald P; Dethmers-Ausema, Albertina et al. (2015) Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice. Am J Physiol Lung Cell Mol Physiol 308:L96-103
Gould, R W; Dencker, D; Grannan, M et al. (2015) Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice. ACS Chem Neurosci 6:1683-95
Gericke, Adrian; Steege, Andreas; Manicam, Caroline et al. (2014) Role of the M3 muscarinic acetylcholine receptor subtype in murine ophthalmic arteries after endothelial removal. Invest Ophthalmol Vis Sci 55:625-31
Trivellin, Giampaolo; Daly, Adrian F; Faucz, Fabio R et al. (2014) Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 371:2363-74

Showing the most recent 10 out of 56 publications