RESUMO
We have genetically mapped the genes encoding four human adrenergic receptors (ARs) of subtypes alpha 1C, alpha 2A, alpha 2B, and beta 1, which are prototypic G protein coupled receptors that mediate the physiological effects of neurotransmitters, hormones, and drugs. We placed these genes onto the Cooperative Human Linkage Center (CHLC) and Genethon framework maps, within confidence intervals with greater than 1000:1 odds. With multipoint analysis the alpha 1C gene (locus ADRA1C) mapped to the interval between NEFL and D8S283; alpha 2-C4, the gene encoding the alpha 2C AR (locus ADRA2C), mapped to the interval between D4S126 and D4S62; and the alpha 2-C10 (alpha 2A AR)/beta 1 haplotype (loci ADRA2A/ADRB1) mapped to the interval between D10S259 and D10S187. A fifth AR gene, beta 2, yielded significant LOD scores with markers on the long arm of chromosome 5; however, this locus (ADRB2) could not be mapped to any specific interval with odds of greater than 1000:1. The two AR genes that are completely linked, alpha 2-C10 and beta 1, were oriented on their shared 225-kb genomic fragment relative to the direction of transcription, with beta 1 being 5' to alpha 2-C10. The positioning of these genes on high-density framework maps allows them to be tested as candidates in a spectrum of diseases that might involve AR dysfunction.
Assuntos
Mapeamento Cromossômico , Receptores Adrenérgicos/genética , Sequência de Bases , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 5 , Cromossomos Humanos Par 8 , Primers do DNA , Humanos , Dados de Sequência MolecularRESUMO
Genotype-to-phenotype analysis reverses the classical approach to genetic disease in which an unknown genotype is sought for a known phenotype. This paper provides an example of genotype-to-phenotype analysis for the possible psychiatric effects of a missense mutation (H396Q) at a highly conserved residue of the beta 1 subunit gene of the gamma aminobutyric acid type A receptor. DNA samples from 1,507 Caucasians of Western European descent were screened, and 10 heterozygotes for H396Q were identified. These individuals were matched to homozygous normal individuals by age, gender, and length of available medical records. The complete medical records of these 20 individuals were reviewed blindly by two psychiatrists (D.C.S., L.L.H.) to assess psychiatric symptomatology, with an emphasis on anxiety and related disorders. However, no association was found between this missense change at a conserved amino acid and a dominant neuropsychiatric disease phenotype. Thus, this missense change may be neutral or only mildly deleterious, may only cause recessive disease in rare individuals, or may interact epistatically with some other gene(s).
Assuntos
Mutação , Receptores de GABA-A/genética , Idoso , Marcadores Genéticos , Genótipo , Humanos , Transtornos Mentais/genética , Pessoa de Meia-Idade , FenótipoRESUMO
Three subjects afflicted with seasonal affective disorder (winter depression) were treated with 2-hour morning light exposures. Within 2 to 5 days, all responded, and remission of their symptoms was sustained during the 2-month treatment period.
Assuntos
Transtorno Depressivo/terapia , Fototerapia/métodos , Estações do Ano , Adulto , Ritmo Circadiano , Transtorno Depressivo/psicologia , Estudos de Avaliação como Assunto , Feminino , Humanos , Masculino , Escalas de Graduação PsiquiátricaRESUMO
Controversy exists concerning whether receptor down-regulation is involved in the efficacy of antidepressants. Many investigators believe that norepinephrine (NE) receptor down-regulation is more important than serotonin (5-HT) receptor down-regulation. The ability to accurately determine which receptor types or subtypes have been down-regulated has been impaired by the lack of sufficiently specific ligands for labeling these receptor subtypes. Studies that have attempted to examine 5-HT2 receptor down-regulation have used [3H]-ketanserin as the ligand of choice to label 5-HT2 receptors, but this ligand also labels a nondescript site. The binding of [3H]-ketanserin to sites other than 5-HT2 receptors can be examined and controlled for by autoradiographic techniques. The authors briefly review potential problems involved in analyzing receptor binding after antidepressant treatment and present new findings of receptor alterations in rat brain as examined by autoradiographic techniques following chronic exposure to fluoxetine (a selective 5-HT uptake inhibitor that has been shown to be an effective antidepressant). Laboratory animals injected with fluoxetine showed receptor down-regulation (reduced density) in the serotonergic system. A provocative and potentially important finding of this study is that this selective 5-HT uptake blocker also down-regulates beta-adrenergic receptors in the CNS.
Assuntos
Antidepressivos/farmacologia , Autorradiografia , Encéfalo/metabolismo , Proteínas de Transporte , Receptores Adrenérgicos/efeitos dos fármacos , Receptores de Droga , Receptores de Serotonina/efeitos dos fármacos , Serotonina/metabolismo , Animais , Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Relação Dose-Resposta a Droga , Fluoxetina/farmacologia , Humanos , Ketanserina/metabolismo , Ketanserina/farmacologia , Ligantes , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Receptores de Neurotransmissores/efeitos dos fármacos , Receptores de Neurotransmissores/metabolismo , Receptores de Serotonina/metabolismoRESUMO
Fluoxetine, a novel antidepressant compound that potently and selectively inhibits serotonin uptake, was chronically administered to laboratory rats. Using in vitro receptor autoradiographic techniques, we found that the binding of [3H]-dihydroalprenolol [( 3H]-DHA) decreased significantly in frontal cortex layers. Analysis of saturation experiments indicated that the reduction was due to a change in number but not affinity of [3H]-DHA binding sites. The data support the hypothesis that the mechanism of action of most antidepressant compounds involves a change in beta-adrenergic receptor function.
Assuntos
Encéfalo/metabolismo , Fluoxetina/farmacologia , Propilaminas/farmacologia , Receptores Adrenérgicos beta/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Di-Hidroalprenolol , Cinética , Masculino , Ratos , Ratos EndogâmicosRESUMO
Significant advances in linkage studies have occurred the past decade based on the use of polymorphic DNA markers known as restriction fragment length polymorphisms (RFLPs). This approach has led to the chromosomal localization of a number of important genetic diseases, and is being increasingly applied to schizophrenia. We discuss two strategies for performing linkage studies in schizophrenia, one based on methodical testing of the human genome, and the other based on selective use of markers. The selective approach uses data from the mode of transmission, previous linkage studies, cytogenetic studies, association studies, case reports, and candidate genes to identify markers that may have an increased likelihood for linkage.
Assuntos
Ligação Genética/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Marcadores Genéticos/genética , Humanos , Fenótipo , Polimorfismo de Fragmento de RestriçãoRESUMO
In sum, the Park City Conference provided a conducive environment for data presentation and interaction among investigators. Over the past year much progress has been made, including advances in the ascertainment of families, genotyping and analytic methods. A critical mass in the field appears realized and major advances may be forthcoming.
Assuntos
Genética Comportamental , Transtornos Mentais/genética , Transtorno Bipolar/genética , Humanos , Transtorno de Pânico/genética , Esquizofrenia/genéticaRESUMO
In a previous study, a genome scan of a subset of schizophrenia families from Palau, Micronesia gave evidence suggestive of linkage to microsatellite markers at 2p13-14. In addition, in a large extended multiplex pedigree (K1583), an 11 cM 2p13-14 haplotype segregated with the illness in eight distantly related schizophrenics. The haplotype region includes a neutral amino acid transporter, ASCT1. We mutation-screened the coding region, flanking intronic sequence and 5'-untranslated region of this transporter in affected members of K1583, two Palauan controls and one Caucasian control. Most polymorphisms were found to be silent or common to all samples scanned. A G/A heterozygote within intron 3 was found in one schizophrenic member of K1583, but was not found in any of the other affected members of K1583. A G/A heterozygote within intron 6 was found in two of six schizophrenics tested in K1583, and in one control. As none of the sequence polymorphisms segregated with illness in the eight schizophrenics, it is unlikely that changes in the 5'-untranslated region, coding sequence or flanking intronic sequence of the ASCT gene predispose to schizophrenia in these families.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 2 , Mutação , Esquizofrenia/genética , Sistemas de Transporte de Aminoácidos , Mapeamento Cromossômico , Éxons , Heterozigoto , Humanos , Micronésia , Mutação de Sentido Incorreto , Fases de Leitura Aberta , Deleção de Sequência , População Branca/genéticaRESUMO
Sertraline, a potent and selective inhibitor of serotonin uptake, was chronically administered to laboratory rats. Using in vitro receptor autoradiographic techniques, we found that the binding of [3H]dihydroalprenolol ([3H]DHA) was reduced in cortex layers IV-VI. Results of a saturation experiment indicated that the reduction in cortex layer IV was due to a change in number but not affinity of beta-adrenergic receptors.
Assuntos
1-Naftilamina/administração & dosagem , Lobo Frontal/metabolismo , Naftalenos/administração & dosagem , Lobo Parietal/metabolismo , Receptores Adrenérgicos beta/metabolismo , Serotonina/metabolismo , 1-Naftilamina/análogos & derivados , Animais , Autorradiografia , Di-Hidroalprenolol/metabolismo , Lobo Frontal/efeitos dos fármacos , Técnicas In Vitro , Masculino , Lobo Parietal/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos beta/efeitos dos fármacos , SertralinaRESUMO
1. Five minute bright light exposures reduced plasma levels of melatonin in eight normal subjects. 2. No significant change in ACTH levels occurred. 3. These results raise the possibility that short intense light exposures can synchronize circadian rhythms as well as benefit patients with seasonal affective disorder. They also indicate that short pulses of bright light do not affect pituitary ACTH production.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Luz , Melatonina/sangue , Adulto , Humanos , Masculino , Fatores de TempoRESUMO
We examined the effects of the "introductory placebo washout" technique by reanalyzing the results of a recent trial of an experimental antidepressant. At the beginning, all patients were placed on placebo in a single-blind design. Patients who were rated as placebo responders with the physician-administered Hamilton Rating Scale for Depression (HRSD) were excluded from the trial. In spite of this technique, an alternative measure of depression indicated that many patients with a positive response to placebo had been entered in the trial. In the reanalysis, elimination of these "hidden placebo responders" did not lower the final placebo response rate and actually diminished the differences observed at the end of the study between the active treatment and placebo groups. These data suggest that the introductory placebo washout may have unpredictable, possibly confounding effects on patient samples in trials of antidepressant agents.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Fluoxetina/uso terapêutico , Imipramina/uso terapêutico , Efeito Placebo , Ensaios Clínicos como Assunto , Transtorno Depressivo/psicologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Escalas de Graduação PsiquiátricaRESUMO
The authors review evidence suggesting that some depressed patients have disturbances in serotonin metabolism. Research supporting the serotonin hypothesis includes: cerebrospinal fluid studies; postmortem examination of neurotransmitters, their metabolites, and their receptors; platelet studies; neuropharmacologic data; neuroendocrine perturbations; and reports that serotonin precursor compounds (tryptophan and 5-hydroxytryptophan) may benefit some depressed patients. The authors conclude that better designed studies are needed to test whether serotonin precursor compounds have antidepressant properties.
Assuntos
Transtorno Depressivo/etiologia , Neurotransmissores/uso terapêutico , Serotonina/metabolismo , 5-Hidroxitriptofano/metabolismo , 5-Hidroxitriptofano/uso terapêutico , Antidepressivos Tricíclicos/metabolismo , Plaquetas/metabolismo , Química Encefálica , Transtorno Depressivo/tratamento farmacológico , Feminino , Humanos , Hidrocortisona/metabolismo , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Levodopa/uso terapêutico , Masculino , Norepinefrina/deficiência , Receptores de Neurotransmissores/metabolismo , Serotonina/deficiência , Tireotropina/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , Triptofano/metabolismo , Triptofano/uso terapêuticoRESUMO
In a double-blind, placebo-controlled study the authors found that fluoxetine, a potent and selective inhibitor of serotonin reuptake, was an effective antidepressant in moderately depressed, ambulatory outpatients. Typical adverse effects reported by patients treated with fluoxetine included agitation, nausea, fatigue, and insomnia. Compared to imipramine, fluoxetine was associated with fewer complaints of dry mouth, constipation, and dizziness.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Fluoxetina/uso terapêutico , Propilaminas/uso terapêutico , Adulto , Assistência Ambulatorial , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Fluoxetina/efeitos adversos , Humanos , Imipramina/efeitos adversos , Imipramina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Distribuição AleatóriaRESUMO
Alterations in serotonin metabolism may be an important factor in the etiology and treatment of depression. In this regard, 5-hydroxytryptophan (5-HTP), a serotonin precursor, has been given to patients with depression. Although a review of these studies suggests that 5-HTP possesses antidepressant properties, additional trials are clearly indicated. Following a discussion of the pharmacology of 5-HTP, the authors highlight adverse effects associated with its administration to depressed patients, neurologic subjects, and normal individuals. Relatively few adverse effects are associated with its use in the treatment of depressed patients.
Assuntos
5-Hidroxitriptofano/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , 5-Hidroxitriptofano/efeitos adversos , 5-Hidroxitriptofano/metabolismo , Carbidopa/metabolismo , Ensaios Clínicos como Assunto , HumanosRESUMO
We have determined the genetic location of the human gene encoding phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholamine pathway catalyzing the synthesis of epinephrine (adrenaline) from norepinephrine. This gene is linked to DNA markers on the long arm of chromosome 17, q21-q22, most closely to the DNA markers MFD15 (D17S250) (Zmax = 15.0, theta = 0.065) and fLB17.1 (Zmax = 14.6, theta = 0.045). Multipoint linkage analysis placed the PNMT locus in the interval fLB17.1-CMM86 (D17S74), at 4 centiMorgans (cM) distal to fLB17.1, and at 17 cM proximal to CMM86. Mapping of the PNMT gene will provide the basis for genetic linkage studies in families with disease which might pathogenetically involve this enzyme. The human chromosomal region 17q21-22 identified here to harbour the PNMT gene may be syntenic to the chromosomal region in the stroke-prone spontaneously hypertensive rat (SHR-SP) recently linked to blood-pressure regulation. As an increase of PNMT activity has been associated with the development of hypertension in SHR-SP, it will be of interest to perform comparative mapping of the PNMT gene.