phosphorus-radioisotopes and Bipolar-Disorder

Topics: Bipolar Disorder; Brain; Calcium; Cerebrovascular Circulation; DNA, Mitochondrial; Humans; Magnetic Resonance Spectroscopy; Mitochondria; Models, Neurological; Mutation; Neuronal Plasticity; Phosphorus Radioisotopes

Magnetic resonance spectroscopy (MRS) is a non-invasive tool for in vivo chemical analysis that has been applied to neurobiological or psychopharmacological studies of affective disorders. Studies employing 31P-MRS and 1H-MRS have indicated possible abnormalities in membrane phospholipid metabolism, high-energy phosphate metabolism, and intracellular pH in affective disorders. They have also suggested that lithium increases the phosphomonoester (possibly inositol-1-phosphate) peak in the brain but does not increase that of choline-containing compounds in the brain. Studies employing 7Li-MRS and 19F-MRS have elucidated the pharmacokinetic properties of lithium, fluoxetine, and fluvoxamine in the brain in patients treated with these drugs.

Topics: Affect; Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Basal Ganglia; Bipolar Disorder; Brain Chemistry; Depression; Energy Metabolism; Fluorine Radioisotopes; Frontal Lobe; Humans; Hydrogen; Lithium; Magnetic Resonance Spectroscopy; Membrane Lipids; Mood Disorders; Phosphorus Radioisotopes; Radioisotopes

In the present study we have investigated the cAMP-dependent phosphorylation system in platelets of euthymic bipolar patients and healthy volunteers before and after 15 days of lithium treatment. The results showed that 15 days of lithium treatment enhanced the basal and the cAMP-stimulated 32P incorporation in the 22 and 38 kDa phosphoproteins in bipolar patients, but not in healthy subjects. Moreover, we provided further evidence of increased phosphorylation in the 22 kDa platelet phosphoprotein in untreated euthymic bipolar patients when compared with controls. Overall, these findings suggest an implication of protein phosphorylation in the biochemical action of lithium and in the pathophysiology of bipolar disorder.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Blood Platelets; Cyclic AMP; Humans; Lithium; Male; Phosphorus Radioisotopes; Phosphorylation

Guanine nucleotide binding proteins (G proteins) have been implicated in the pathophysiology of bipolar affective disorder. In the present investigation receptor-mediated G protein activation and changes in G protein trimeric state were examined in frontal cortical membranes obtained from postmortem brains of bipolar affective disorder subjects and from age-, sex-, and postmortem interval-matched controls. Stimulation of cortical membranes with serotonin, isoproterenol, or carbachol increased guanosine 5'-O-(3-[35S]thiophosphate) ([35S]GTP gamma S) binding to specific G alpha proteins in a receptor-selective manner. The abilities of these receptor agonists to stimulate the binding of [35S]GTP gamma S to the G alpha proteins was enhanced in membranes from bipolar brains. Immunoblot analyses showed increases in the levels of membrane 45- and 52-kDa G alpha S proteins but no changes in the amounts of G alpha i, G alpha o, G alpha Z, G alpha q/11, or G beta proteins in membrane or cytosol fractions of bipolar brain homogenates. Pertussis toxin (PTX)-activated ADP-ribosylations of G alpha i and G alpha o were enhanced by approximately 80% in membranes from bipolar compared with control brains, suggesting an increase in the levels of the trimeric state of these G proteins in bipolar disorder. Serotonin-induced, magnesium-dependent reduction in PTX-mediated ADP-ribosylation of G alpha i/G alpha o in cortical membranes from bipolar brains was greater than that observed in controls, providing further evidence for enhanced receptor-G protein coupling in bipolar brain membranes. In addition, the amounts of G beta proteins that coimmunoprecipitated with the G alpha proteins were also elevated in bipolar brains. The data show that in bipolar brain membrane there is enhanced receptor-G protein coupling and an increase in the trimeric state of the G proteins. These changes may contribute to produce exaggerated transmembrane signaling and to the alterations in affect that characterize bipolar affective disorder.

Topics: Adenylyl Cyclases; Aged; Aged, 80 and over; Autopsy; Autoradiography; Bipolar Disorder; Brain Chemistry; Female; Frontal Lobe; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Humans; Immunoblotting; Male; Membrane Proteins; Middle Aged; Phosphorus Radioisotopes; Precipitin Tests; Receptors, Cell Surface; Receptors, Serotonin; Serotonin Receptor Agonists; Sulfur Radioisotopes

The aim of the study was to assess cAMP-dependent endogenous phosphorylation in platelets from euthymic bipolar patients.. Platelets from 10 drug-free euthymic patients with bipolar disorder were compared with those from 10 age- and sex-matched healthy subjects. Basal and cAMP-stimulated protein phosphorylation was examined in each group.. Endogenous phosphorylation in both the healthy volunteers and the bipolar patients was significantly stimulated by cAMP; the major polypeptides had apparent molecular weights of 38 and 22 kDa. The cAMP-stimulated 32P incorporation differed between the bipolar patients and the comparison subjects only in the 22-kDa band.. These data suggest a possible role of cAMP-dependent protein phosphorylation in the pathophysiology of bipolar disorder.

Topics: Adult; Biomarkers; Bipolar Disorder; Blood Platelets; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Humans; Male; Phosphorus Radioisotopes; Phosphorylation

This study examines recent suggestions from a number of investigators that signal-transducing guanine nucleotide-binding (G) proteins may be involved in the pathophysiology of bipolar affective disorder and may represent molecular targets for lithium's mood-stabilizing actions.. We used selective antibodies to quantitate the levels of the G protein alpha subunits that regulate adenylate cyclase activity (G alpha s and G alpha i2) and phosphoinositide turnover (G alpha q/11). We also quantitated levels of pertussis toxin-catalyzed phosphate 32-labeled adenosine diphosphate ([32P]ADP) ribosylation in platelet and leukocyte membranes from a group of 14 untreated (predominantly manic) patients with bipolar affective disorder, 20 lithium-treated euthymic patients with bipolar affective disorder, and 11 healthy controls.. In both tissues, the immunolabeling of the 45-kd form of G alpha s was higher in the bipolar affective disorder group considered as a whole (treated or untreated) compared with controls, effects that reached statistical significance in the leukocyte membranes. There were no significant differences in the immunolabeling of G alpha i1/2, G alpha q/11, or pertussis toxin-catalyzed [32P]ADP ribosylation in either tissue in the untreated bipolar affective disorder group compared with controls. In both tissues, lithium-treated subjects demonstrated lower levels of G alpha q/11 and higher levels of pertussis toxin-catalyzed [32P]ADP-ribosylation, which reached significance in the platelet membranes.. Our results are complementary to the previously reported findings of elevated G alpha s levels in postmortem brain tissue form patients with bipolar affective disorder and in mononuclear leukocytes obtained from depressed patients with bipolar (but not unipolar) affective disorder. The significantly higher levels of pertussis toxin-catalyzed [32P]ADP ribosylation in the subjects receiving long-term lithium-treatment replicates our findings in rat cortex and in healthy volunteers and adds to the growing body of evidence implicating G alpha i as a target of lithium's actions.

Topics: Adenosine Diphosphate Ribose; Adenylate Cyclase Toxin; Adult; Bipolar Disorder; Blood Platelets; Female; GTP-Binding Proteins; Humans; Immunoblotting; Leukocytes; Lithium; Male; Middle Aged; Pertussis Toxin; Phosphorus Radioisotopes; Virulence Factors, Bordetella