RESUMEN
Using synaptosomes prepared from whole rat brain, the spontaneous, calcium-independent, and calcium-dependent release of glutamate and GABA was assessed. Time intervals of 1-30 seconds were studied. Spontaneous release of glutamate (but not GABA) was elevated by 10 microM NMDA or AMPA by thirty seconds. This stimulation was partially calcium-dependent. Calcium-dependent release induced by 30 mM KCl was biphasic, confirming previous findings. This release was stimulated at all time periods by the presence of 10 microM NMDA or AMPA in an antagonist-sensitive manner. These data suggest that glutamate and GABA are released from vesicular stores in rat synaptosomes and that some of this release is modulated by presynaptic glutamate receptors.
Asunto(s)
Aminoácidos/metabolismo , Encéfalo/metabolismo , Sinapsis/fisiología , Sinaptosomas/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Animales , Encéfalo/efectos de los fármacos , Calcio/farmacología , Glutamatos/metabolismo , Ácido Glutámico , Ácido Iboténico/análogos & derivados , Ácido Iboténico/farmacología , Cinética , Masculino , N-Metilaspartato/farmacología , Cloruro de Potasio/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Endogámicas , Sinaptosomas/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Previous studies from our laboratory indicated that the veratridine-induced release of glutamate and GABA from synaptosomes derived from brains of schizophrenics was decreased. In the present study, synaptosomes were prepared from frozen brain samples from schizophrenics and from controls. Stimulation by 10 mumol/L 2-amino-3-hydroxy-5-methoxylisoxazole-4-propionic acid (AMPA) produced equal glutamate release from both groups. Release induced by either 10 mumol/L kainic acid (KA) or n-methyl-d-asparate (NMDA) was reduced significantly in the preparations derived from schizophrenics. Similarly, the amount of GABA released by 50 mumol/L glutamate was also reduced in the schizophrenic-derived synaptosomes. However, in membranes derived from the crude synaptosomal pellet, no differences between the controls and schizophrenics were observed in measures of total glutamate binding or its displacement by NMDA. The data demonstrate a deficiency in NMDA (and possibly KA) receptor functioning schizophrenics and support the "second-generation" theories of schizophrenia as a glutamatergic deficiency disorder.
Asunto(s)
Encéfalo/fisiopatología , Glutamatos/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Sinaptosomas/fisiología , Técnicas de Cultivo , Ácido Glutámico , Humanos , Masculino , Receptores de Glutamato , Receptores de Neurotransmisores/fisiología , Lóbulo Temporal/fisiopatología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
In several previous studies, we reported significantly higher plasma serine concentrations in psychotic (and schizophrenic) subjects compared with nonpsychotic and control subjects. In those studies, we used a gas chromatography technique to assay the amino acids. Perry and Hanson (1985), using cation-exchange chromatography to assay plasma amino acids, found no differences in the plasma serine concentrations of controls compared with schizophrenic patients. They criticized our work on technical grounds and suggested that some other substance was co-eluting with the gas chromatographic serine peaks in our assays. We have now examined the plasma of schizophrenic and control subjects with gas chromatography-mass spectrometry (GC-MS), where accurate amino acid quantitation relative to a known internal standard can be achieved. The results show that the plasma serine concentrations of schizophrenic patients are significantly higher than those of controls. Also, plasma glycine concentrations are significantly higher in schizophrenic patients compared with controls.
Asunto(s)
Cromatografía de Gases y Espectrometría de Masas , Esquizofrenia/sangre , Psicología del Esquizofrénico , Serina/sangre , Adulto , Antipsicóticos/uso terapéutico , Femenino , Glicina/sangre , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Esquizofrenia/tratamiento farmacológicoRESUMEN
Studies of amino acid release were carried out using frozen sections from brains of schizophrenics and controls. Synaptosomes were prepared via differential centrifugation in Ficoll allowing the veratridine-induced release of aspartate, glutamate, glycine, and GABA to be measured. The release of glutamate and gamma-aminobutyric acid (GABA) was reduced in the synaptosomes from schizophrenics. This decrease could be reversed partially by pre-incubation of the synaptosomes with haloperidol. Additionally, the activity of glutamate decarboxylase was decreased and partially restored by haloperidol pre-incubation. These data are consistent with the hypothesis of a glutamatergic/GABAergic deficit in schizophrenia.
Asunto(s)
Glutamatos/deficiencia , Esquizofrenia/metabolismo , Anciano , Ácido Aspártico/metabolismo , Química Encefálica , Corteza Cerebral/química , Corteza Cerebral/metabolismo , Femenino , Glutamato Descarboxilasa/metabolismo , Ácido Glutámico , Haloperidol , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Sinaptosomas/química , Sinaptosomas/metabolismo , Veratridina , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We studied the kinetics of the enzyme serine hydroxymethyl transferase (SHMT) and the concentration of its metabolic substrates serine and glycine, in the postmortem brains of controls and schizophrenics. The Km of SHMT, and the concentration of serine and glycine were all significantly higher in the temporal lobes of brain tissues from schizophrenics than in those from controls. These differences were not observed in the frontal lobe specimens. Neuroleptics, age, sex and autolysis time did not contribute to these differences. The role of SHMT deficiency in schizophrenia is discussed in relation to the production of glycine and 1-carbon units from which purines and thereby adenosine is produced. Both glycine and adenosine are potent neuromodulatory substances for the release of dopamine and glutamate, neurotransmitters which have been implicated in the pathophysiology of schizophrenia.