RESUMEN
We used microarray analysis of acute nicotine responses in mouse brain to choose rationale candidates for human association studies on tobacco smoking and nicotine dependence (ND). Microarray studies on the time-course of acute response to nicotine in mouse brain identified 95 genes regulated in ventral tegmental area. Among these, 30 genes were part of a gene network, with functions relevant to neural plasticity. On this basis and their known roles in drug abuse or synaptic plasticity, we chose the genes RhoA and Ywhag as candidates for human association studies. A synteny search identified human orthologs and we investigated their role in tobacco smoking and ND in a human case-control association study. We genotyped five and three single nucleotide polymorphisms from the RhoA and Ywhag genes, respectively. Both single marker and haplotype analyses were negative for the Ywhag gene. For the RhoA gene, rs2878298 showed highly significant genotypic association with both smoking initiation (SI) and ND (P = 0.00005 for SI and P = 0.0007 for ND). In the allelic analyses, rs2878298 was only significant for SI. In the multimarker haplotype analyses, significant association with SI was found for the RhoA gene (empirical global P values ranged from 9 x 10(-5) to 10(-5)). In all multimarker combinations analyzed, with or without inclusion of the single most significant marker rs2878298, identical risk and protective haplotypes were identified. Our results indicated that the RhoA gene is likely involved in initiation of tobacco smoking and ND. Replication and future model system studies will be needed to validate the role of RhoA gene in SI and ND.
Asunto(s)
Fumar/genética , Tabaquismo/genética , Proteína de Unión al GTP rhoA/genética , Animales , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Haplotipos , Humanos , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Valores de Referencia , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/metabolismo , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
A homozygous CGRP-/- mouse line was generated by the targeted disruption of exon 5 in the calcitonin/alphaCGRP gene using homologous recombination. The mutant mice lack alphaCGRP mRNA. Furthermore CGRP immunoreactivity almost completely disappears from the spinal cord and is not at all observed in spinal ganglia and muscle synapses. However, motor end plates were still detected by acetylcholinesterase staining. Antinociceptive behavior tested by the tail flick and hot plate tests did not significantly differ in mutant and wild-type mice, except when challenged by morphine. Paradoxically, morphine analgesia was reduced in mutant mice compared with controls in the tail flick test, but not in the hot plate test. Thus, alphaCGRP differentially modulates opiate pain pathways.
Asunto(s)
Analgésicos Opioides/farmacología , Péptido Relacionado con Gen de Calcitonina/genética , Morfina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Southern Blotting , Western Blotting , Desoxirribonucleasa HindIII/metabolismo , Femenino , Genoma , Calor , Inmunohistoquímica , Masculino , Ratones , Mutación/fisiología , Dimensión del Dolor/efectos de los fármacos , ARN/análisis , ARN/genética , Mapeo RestrictivoRESUMEN
COR3224 is a new 2-amino-2 oxazoline derivative with antidepressant properties. The distribution, excretion and metabolism of radiochemically labelled 14C-COR3224 has been investigated in the rat after intravenous injection. The compound was widely distributed and rapidly excreted. Hydroxylation and sulphate conjugation are involved in the COR3224 elimination.