RESUMEN
A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the alpha4beta2, ganglionic (alpha3beta4) and muscle subtypes. The transgenic th(tk-)/th(tk-) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.
Asunto(s)
Conducta Animal/efectos de los fármacos , Benzofuranos/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Neuronas/metabolismo , Agonistas Nicotínicos/uso terapéutico , Quinuclidinas/uso terapéutico , Receptores Nicotínicos/fisiología , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Animales , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Benzofuranos/farmacología , Clozapina/farmacología , Clozapina/uso terapéutico , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/psicología , Conducta Exploratoria/efectos de los fármacos , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Agonistas Nicotínicos/farmacología , Regiones Promotoras Genéticas , Quinuclidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/biosíntesis , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/metabolismo , Conducta Social , Tirosina 3-Monooxigenasa/genética , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
C1R.Aw68 delta 242 is a human B cell line expressing a mutant class I molecule that is defective in assembly and transport at 37 degrees C but is stably expressed at room temperature. This cell line has been utilized to study the conformation dependence of MHC class I in the modulation of target cell sensitivity to natural killing. Surface expression of MHC class I molecules was monitored by the antibodies W6/32 (detecting a pan-class I specificity that is beta 2-microglobulin and conformation dependent) and HC.10 (detecting free HLA-B heavy chain and a subset of HLA-A heavy chains). C1R.Aw68 delta 242 was cultured at reduced temperature to induce cell surface expression of class I molecules, and then the temperature was shifted to 37 degrees C. During the first 2 h at 37 degrees C, C1R.Aw68 delta 242 displayed a higher level of HC.10 reactivity than W6/32. Conjugation of C1R.Aw68 delta 242 to NK cells correlated inversely with W6/32 expression, but not with HC.10 reactivity as revealed by flow cytometry. The sensitivity of the C1R.Aw68 delta 242 cells to NK-mediated lysis was also examined as a function of temperature, and the level of C1R.Aw68 delta 242 cytolysis correlated inversely with W6/32 expression but not HC.10. The fact that both the conjugation rate and target cell cytolysis increased with decreased reactivity with the conformation-dependent antibody W6/32 and not with HC.10, is consistent with the hypothesis that NK cell inhibitory receptors (KIR) detect a conformation-dependent epitope(s).