ABSTRACT
BACKGROUND: Glutamatergic dysregulation has been documented in schizophrenia but has received less systematic study in affective illness. METHODS: Cerebrospinal fluid (CSF) levels of the excitatory amino acids glutamate (Glu) and aspartate (Asp) and the N-methyl-D-aspartate (NMDA) receptor modulator, glycine (GLY) were measured by high performance liquid chromatography in 32 patients with refractory affective disorder (16 female/16 male, 12 bipolar I, 12 bipolar II, and 8 unipolar) and in 14 age-matched controls. RESULTS: There was a significant reduction in CSF glutamate and glycine in patients versus controls. A diagnosis by sex interaction was present for CSF glycine with lower levels in female patients compared to female controls. Levels of the excitatory amino acids were highly inter-correlated in patients, but not in controls. In patients studied after 6 weeks of lamotrigine, there was a trend for CSF glutamate levels to increase. CONCLUSIONS: These data suggest that in patients with refractory affective disorder, excitatory amino acids are dysregulated, as exemplified both by the decreased CSF glutamate and glycine and their high intercorrelation compared to controls. Further controlled study of glutamatergic dysregulation and its relationship to the pathophysiology of affective disorders and potential mechanism of action of mood stabilizers appears indicated.
Subject(s)
Anticonvulsants/therapeutic use , Antidepressive Agents/therapeutic use , Antimanic Agents/therapeutic use , Bipolar Disorder/cerebrospinal fluid , Depressive Disorder, Major/cerebrospinal fluid , Glutamic Acid/cerebrospinal fluid , Glycine/cerebrospinal fluid , Adult , Aspartic Acid/cerebrospinal fluid , Chromatography, High Pressure Liquid , Depressive Disorder, Major/drug therapy , Drug Resistance , Electroconvulsive Therapy , Female , Humans , Male , Middle Aged , N-Methylaspartate/cerebrospinal fluid , Statistics as TopicABSTRACT
Serotonin activation of 5-HT2A receptors facilitates depolarization of neocortical neurons by N-methyl-D-aspartate (NMDA). Using grease-gap recordings from an in vitro cortical wedge preparation we have examined whether agents which raise the concentration of intracellular Ca2+ mimic the facilitation. Perfusing A23187, cyclopiazonic acid or thapsigargin selectively facilitate the NMDA depolarization of cortical neurons in a concentration-dependent manner. Buffering intracellular Ca2+ by perfusing BAPTA-AM eliminates the serotonin, cyclopiazonic acid and thapsigargin induced facilitation. We conclude that a rise in intracellular Ca2+ is both necessary and sufficient to account for facilitating the NMDA depolarization following activation of 5-HT2A receptors.
