RESUMEN
Using an indirect subtraction binding technique and human postmortem tissue, several laboratories reported finding increases in dopamine D4 receptors in caudate nuclei of schizophrenic patients, although others have not replicated these findings. NGD-94-1 is a selective D4 antagonist with low affinity for the D2 and D3 receptors. [3H]NGD-94-1 has been used in this study to directly determine the density of D4 receptors in normals (n = 13) and schizophrenic subjects (n = 7) off antipsychotic drugs for at least 3 months prior to death, or on antipsychotic (n = 7) drugs at the time of death. Human postmortem coronal brain sections were incubated with [3H]NGD-94-1 and autoradiograms developed; and binding in pertinent regions was quantified. In normals, the highest density of [3H]NGD-94-1 binding was in the hippocampus (68 fmol mg(-1), temporal (33), insular (30), and entorhinal cortices (24.9). Significant increases in [3H]NGD-94-1 density in schizophrenics (n = 14) vs normals (n = 13) were observed in the entorhinal cortex (46%) at both low and high magnifications. The increases observed in the schizophrenics were found in both schizophrenics off antipsychotic drugs for at least 3 months prior to death and those on antipsychotic drugs at the time of death. Thus, the changes may be disease-related and not a consequence of pharmacological treatment. No significant differences were found between the two schizophrenic groups in any brain area studied.
Asunto(s)
Antagonistas de Dopamina/farmacocinética , Imidazoles/farmacocinética , Pirimidinas/farmacocinética , Receptores de Dopamina D2/análisis , Esquizofrenia/metabolismo , Adulto , Antipsicóticos/uso terapéutico , Autopsia , Autorradiografía/métodos , Corteza Entorrinal/metabolismo , Femenino , Hipocampo/metabolismo , Humanos , Masculino , Especificidad de Órganos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Valores de Referencia , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/patología , TritioRESUMEN
[3H]Neurotensin binding and autoradiographic techniques were used to determine the distribution and density of neurotensin receptors in normal and schizophrenic postmortem brain tissue. Coronal hemi-brain blocks of tissue were cut at the level of the caudate and hippocampus from frozen brain tissue obtained from normal individuals with no known psychiatric or neurologic illnesses and from schizophrenic subjects off- or on-antipsychotic drugs at the time of death. Each hemi-block was further divided, sectioned, thaw mounted on to slides, incubated with [3H]neurotensin and apposed to film. Digitized images were analyzed for binding densities. Areas of intense binding include the substantia nigra, the entorhinal cortex, superficial layers of the cingulate, middle frontal, and insular cortices; and with moderate binding in nucleus accumbens, and caudate. Schizophrenic patients off- (3 months or more) or on-antipsychotic drugs at the time of death were tested; all patients showed a reduced level of neurotensin receptors in the caudate (68% of normals), cingulate (34%) and prefrontal cortices (25%).
Asunto(s)
Encéfalo/metabolismo , Neurotensina/metabolismo , Receptores de Neurotensina/análisis , Esquizofrenia/metabolismo , Adulto , Edad de Inicio , Anciano , Autopsia , Autorradiografía , Encéfalo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Especificidad de Órganos , Receptores de Neurotensina/metabolismo , Valores de Referencia , Esquizofrenia/patología , TritioRESUMEN
The density of the presumed dopamine D4 receptor ([3H]YM-09151-2 minus [3H]raclopride), as well as the densities of the two ligands themselves were compared in various areas of cerebral tissue from normal versus schizophrenic subjects off or on antipsychotic drugs at the time of death. Using autoradiographic techniques, and analyzing various brain areas, no differences were found in the density of the D4 receptor, nor were differences found between the groups, in any brain region, in the amount of bound [3H]YM-09151-2 or [3H]raclopride. There were, therefore, no differences in the density of the D3-type receptors, including the D4 receptor, in normal and schizophrenic subjects off or on antipsychotic drugs at the time of death.
Asunto(s)
Encéfalo/metabolismo , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D2/metabolismo , Salicilamidas/farmacología , Esquizofrenia/metabolismo , Adulto , Unión Competitiva , Encéfalo/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Racloprida , Receptores de Dopamina D2/efectos de los fármacosRESUMEN
The affinity and intrinsic activity of dopamine receptor agonists were determined at the human dopamine hD21 and hD4.4 receptors. (-)-3-Hydroxy-N-n-propylpiperidine ((-)3-PPP) had an intrinsic activity of 46% and 83%, whereas (+)-N-propylnorapomorphine ((+)-NPA) had intrinsic activities of 61% and 58% at the dopamine hD21 and hD4.4 receptors, respectively. Affinities also varied. A single, or multiple, dopamine D2-type receptor(s) may be involved in schizophrenia and agonists are being tested as therapy. Understanding their properties at the individual dopamine D2-family receptors is important.