RESUMEN
Muscarinic receptors have been implicated in the regulation of cognition and psychosis based on pharmacological evidence from pre-clinical and clinical studies. Muscarinic agonists have shown promise in the clinic in improving cognition and reducing psychotic episodes in Alzheimer's patients. However, lack of selective muscarinic ligands has limited their use due to troublesome side effects observed at higher doses. Without selective ligands, it has been difficult to assign a specific muscarinic receptor subtype to these high order mental processes. Recent development of muscarinic receptor knockout mice has provided additional tools to investigate cognition and psychosis in behavioral assays and to determine the receptor subtypes associated with parasympathomimetic physiology. Biochemical studies indicate that the M1 receptor plays a significant role in regulating G alpha q-mediated signal transduction in the hippocampus and cortex. Behavioral studies suggest that the M4 receptor is involved in movement regulation and prepulse inhibition of the startle reflex, a measure of attention. These findings support a role for the development of M1 and M4 receptor agonists for diseases in which symptoms include cognitive impairment and psychotic behaviors.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Neuronas/metabolismo , Receptores Muscarínicos/metabolismo , Esquizofrenia/fisiopatología , Animales , Fraccionamiento Celular , Línea Celular , Membrana Celular/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Masculino , Memoria/fisiología , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Oxotremorina/farmacología , Fenciclidina/farmacología , Ensayo de Unión Radioligante/métodos , Receptores Muscarínicos/genética , Transducción de Señal/fisiologíaRESUMEN
We describe an apparatus for the coincident observation of both outgoing electrons in an electron impact ionization, or (e,2e), experiment. The device employs ten detectors arranged such that every pair corresponds to a different set of momenta for the outgoing electrons intercepted by that pair. By simultaneously monitoring the output from all ten detectors it is possible to perform 25 simultaneous (e,2e) experiments. The results of these experiments can be compared without considering temporal variations of source conditions.