Assuntos
Carcinoma Basocelular/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Medição de Risco , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Queensland/epidemiologia , Sensibilidade e EspecificidadeRESUMO
Chronic alcohol misuse by human subjects leads to neuronal loss in regions such as the superior frontal cortex (SFC). Propensity to alcoholism is associated with several genes. gamma-Aminobutyric acid (GABA)(A) receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the regional presentation of GABA(A) and glutamate-NMDA (N-methyl-d-aspartate) receptors in SFC. Autopsy tissue was obtained from alcoholics without comorbid disease, alcoholics with liver cirrhosis, and matched controls. ADH1C, DRD2B, EAAT2, and APOE genotypes modulated GABA(A)-beta subunit protein expression in SFC toward a less-effective form of the receptor. Most genotypes did not divide alcoholics and controls on glutamate-NMDA receptor pharmacology, although gender and cirrhosis did. Genotype may affect amino acid transmission locally to influence neuronal vulnerability.
Assuntos
Alcoolismo/genética , Encéfalo/metabolismo , Cirrose Hepática Alcoólica/genética , Receptores de GABA-A/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Alcoolismo/metabolismo , Encéfalo/efeitos dos fármacos , Estudos de Casos e Controles , Córtex Cerebral/metabolismo , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Expressão Gênica , Humanos , Cirrose Hepática Alcoólica/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de GABA-A/metabolismoRESUMO
Chronic alcoholism leads to localized brain damage, which is prominent in superior frontal cortex but mild in motor cortex. The likelihood of developing alcohol dependence is associated with genetic markers. GABAA receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the localized expression of glutamate and gamma-aminobutyric acid (GABA) receptors to influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy from alcoholics without alcohol-related disease, alcoholics with cirrhosis, and matched controls. DRD2A, DRD2B, GABB2, EAAT2, and 5HTT genotypes did not divide alcoholic cases and controls on N-methyl-d-aspartate (NMDA) receptor parameters. In contrast, alcohol dehydrogenase (ADH)3 genotype interacted significantly with NMDA receptor efficacy and affinity in a region-specific manner. EAAT2 genotype interacted significantly with local GABAA receptor beta subunit mRNA expression, and GABB2 and DRD2B genotypes with beta subunit isoform protein expression. Genotype may modulate amino acid transmission locally so as to mediate neuronal vulnerability. This has implications for the effectiveness of pharmacological interventions aimed at ameliorating brain damage and, possibly, dependence.
Assuntos
Alcoolismo/genética , Encéfalo/metabolismo , Neurotransmissores/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Alcoolismo/metabolismo , Aminoácidos/metabolismo , Análise de Variância , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genótipo , Humanos , Cirrose Hepática Alcoólica/genética , Cirrose Hepática Alcoólica/metabolismo , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Isoformas de Proteínas/genética , RNA Mensageiro/análise , Receptores de GABA-A/genética , Receptores de Glutamato/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
GABA(A) receptor sites were characterised in cerebral cortex tissue samples from deceased neurologically normal infants who had come to autopsy during the third trimester of pregnancy. Pharmacological parameters were obtained from homogenate binding studies which utilised the 'central-type' benzodiazepine ligands [3H]diazepam and [3H]flunitrazepam, and from the GABA activation of [3H]diazepam binding. It was found that the two radioligands behaved differently during development. The affinity of [3H]flunitrazepam for its binding site did not vary significantly between preparations, whereas the [3H]diazepam K(D) showed marked regional and developmental variations: infant tissues showed a distinctly lower affinity than adults for this ligand. The density of [3H]flunitrazepam binding sites increased approximately 35% during the third trimester to reach adult levels by term, whereas [3H]diazepam binding capacity declined slightly but steadily throughout development. The GABA activation of [3H]diazepam binding was less efficient early in the trimester, in that the affinity of the agonist was significantly lower, though it rose to adult levels by term. The strength of the enhancement response increased to adult levels over the same time-frame. The results strongly suggest that the subunit composition of cortical GABA(A) sites changes significantly during this important developmental stage.