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Biomedical subjects

L T Young

Publications and source records attributed to L T Young.

At least 55 records · Page 3Linked to original sources
PubMed1999

A two-illness model of bipolar disorder.

The current approach to mood disorders is that bipolar disorder, comprising both mania and depression, is a discreet illness distinct from unipolar depression. This formulation has profoundly influenced the approach to understanding the biology and etiology of these disorders, as well as the manner in which the various phases of bipolar disorder are treated. Our new model suggests that bipolar disorder comprises two distinct illnesses, mania and depression, and that bipolar depression is no different from unipolar depression. Studies of clinical syndromes, course of illness, family history and genetics, biological factors, and treatment response data directly or indirectly support this new model.

Antidepressive Agents↗
PubMed1999

G Protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders: effects of diagnosis, suicide, and treatment at the time of death.

Components of cyclic AMP (cAMP) signaling were examined in postmortem cerebral cortex of a well characterized group of patients with mood disorders and nonpsychiatric control subjects. We measured G protein levels, adenylyl cyclase (AC) activity, and CREB levels in cerebral cortex of the subjects with respect to diagnosis, treatment, and suicide. There was no effect of diagnosis on any measure, except for a trend toward decreased stimulated AC activity in subjects with mood disorders relative to control subjects. We also detected a significant effect of suicide on temporal cortex CREB levels in subjects that died as a result of suicide relative to those that did not, which was more evident in patients with major depressive disorder. Bipolar disorder (BD) subjects treated with anticonvulsants at the time of death had decreased temporal cortex CREB levels relative to those not receiving anticonvulsants. Furthermore, we found a trend toward decreased occipital cortex G alpha(s) (short) levels in BD subjects treated with lithium. These results support the hypothesis of altered cAMP signaling in mood disorders and raise the possibility that factors other than diagnosis, such as treatment and suicide, may be relevant to cell-signaling abnormalities reported in the literature.

Adenylyl Cyclases↗
PubMed1999

Platelet protein kinase C alpha levels in drug-free and lithium-treated subjects with bipolar disorder.

Recent studies suggest that protein kinase C (PKC), particularly the alpha isoform, plays an important role in the action of lithium. There is, however, little evidence from patients with bipolar disorder (BD) to support this effect. The present investigation carried out comparative studies of PKC levels in platelets obtained from BD subjects including those with and without lithium treatment. All subjects met DSM-IV criteria for BD type I confirmed by structured interview (SCID-IV). Levels of PKC-alpha isoform in platelets from controls and from BD subjects were measured with immunoblotting analysis. No significant differences were found between controls, drug-free or lithium-treated BD subjects on membrane or cytosolic levels of PKC-alpha or in the membrane-to-cytosol ratio of this protein. The present study suggests that levels of PKC-alpha do not change in the peripheral tissues of BD subjects with or without lithium treatment.

Adult↗
PubMed1999

Family-of-origin characteristics in bipolar disorder: a controlled study.

OBJECTIVE: To assess the family-of-origin characteristics of patients with bipolar disorder relative to those of control subjects. METHOD: Fifty-six euthymic patients meeting research diagnostic criteria for bipolar disorder and 21 control subjects completed the Family Environment Scale (FES) for the family they grew up with. RESULTS: The 2 groups showed strikingly similar profiles on 10 indices of family functioning or structure. CONCLUSIONS: The results do not support the hypothesis that specific family attributes contribute to the development of bipolar disorder.

Adult↗
PubMed1999

Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78.

Differential display polymerase chain reaction was used to identify genes regulated by the mood-stabilizing drug valproate (VPA). Four differentially displayed valproate-regulated gene fragments were isolated in rat cerebral cortex after i.p. injection of sodium VPA (300 mg/kg) for 3 weeks, and their expression was confirmed by Northern and slot blot analysis in rat cerebral cortex and C6 glioma cells. Sequencing analysis revealed three previously unidentified cDNA fragments in addition to a sequence with 100% homology with a molecular chaperone, 78-kDa glucose-regulated protein (GRP78). VPA treatment did not increase mRNA expression of 70-kDa heat shock protein, which is a related stress-induced molecular chaperone protein. All four candidate genes, including GRP78, showed similar VPA concentration-dependent increases in mRNA abundance. Another commonly prescribed mood-stabilizing anticonvulsant, carbamazepine, also increased GRP78 mRNA expression in C6 glioma cells, whereas lithium had no effect at doses up to 2 mM. Immunoblotting revealed that GRP78 protein levels were also increased in C6 glioma cells treated with VPA under the same conditions. Nuclear runoff analysis showed that VPA increased GRP78 gene transcription. Because GRP78 possesses molecular chaperone activity, binds Ca2+ in the endoplasmic reticulum, and protects cells from the deleterious effects of damaged proteins, the present findings suggest that VPA (and possibly carbamazepine) treatment may target one or more of these processes.

Animals↗
PubMed1998

Pre-drug cues modulate morphine tolerance, striatal c-Fos, and AP-1 DNA binding.

To evaluate the molecular mechanisms that mediate the effect of learning on morphine tolerance in rats, we examined striatal c-Fos, and c-Jun protein expression, and AP-1 DNA binding. Morphine paired with a conditioned stimulus (CS) led to analgesic tolerance in the presence of the CS. Rats receiving morphine unpaired with the CS displayed significantly less tolerance than paired morphine animals. Striatal c-Fos protein levels and AP-1 DNA binding activity were increased in rats receiving paired morphine compared with rats that did not receive morphine but not in rats receiving morphine without the CS. No differences were found in c-Jun levels. These results suggest that Pavlovian conditioning may account, in part, for the molecular mechanisms associated with morphine tolerance.

Animals↗
PubMed1998

Differential effects of mood stabilizers on Fos/Jun proteins and AP-1 DNA binding activity in human neuroblastoma SH-SY5Y cells.

Lithium and sodium valproate (VPA) are effective in the treatment of bipolar disorder (BD) and may function through the regulation of signal transduction pathways and transcription factors such as c-fos and c-Jun, which in turn results to changes in gene expression. The long-term efficacy of lithium and VPA in BD suggests that the regulation of gene expression may be an important target for these drugs. Preliminary evidence suggests that c-fos levels and AP-1 binding may be regulated by lithium and VPA, but the results are inconclusive. In the present study, we report differential effects of the two most commonly prescribed mood stabilizers used to treat BD on Fos/Jun protein levels and their AP-1 binding activity in human neuroblastoma SH-SY5Y cells. At therapeutically relevant concentrations, both drugs acutely (<24 h) induced c-Fos immunoreactivity and AP-1 binding. In contrast to lithium, chronic (1 week) treatment with VPA led to continued induction of c-Fos, in addition to induction of c-Jun immunoreactivity and a 33-35 kDa band previously identified as chronic FRA. AP-1 DNA binding activity was also increased after 1 week VPA treatment. These findings suggest that both these mood stabilizers may have an effect on neuronal gene expression of target genes containing the AP-1 consensus sequence in their promoter regions after acute treatment. The present results confirm and extend previous findings on the regulation of c-fos expression and AP-1 binding after administration of mood stabilizers, and further elucidate the mechanisms through which VPA increases AP-1 DNA binding.

Antimanic Agents↗
PubMed1998

Gender differences in patients with bipolar disorder influence outcome in the medical outcomes survey (SF-20) subscale scores.

BACKGROUND: The importance of gender on the course and outcome in bipolar disorder (BD) has been widely acknowledged. The limited data suggest that the prevalence is similar between sexes but that the course of illness may be different. This study investigated gender differences in a clinic sample of patients with BD including a measure of subjects' perception of well-being and functioning. METHODS: Euthymic outpatients attending a mood disorders clinic were systematically assessed. Measurements obtained included SADS-LV, Hamilton Depression Ratings scores, Young Mania Rating scores, and Medical Outcome Survey Short Form 20 items and Global Assessment of Functioning. RESULTS: Women with BD have a later onset of mania, are more likely to have a rapid cycling course, experience mixed episodes, experience more depressive episodes and report more overall impairment in all MOS subscale scores with significant impairment in physical health and pain. CONCLUSIONS: Further investigation and replication of these differences need to be addressed including non-euthymic patients and during a longer period of systematic follow-up.

Adult↗
PubMed1997

Relationship between the five-factor model of personality and unipolar, bipolar and schizophrenic patients.

The purpose of this study was to examine personality differences among three different Axis I disorders-recovered patients with unipolar depression (n = 62), euthymic patients with bipolar disorder (n = 34), and patients with schizophrenia in the residual phase of their illness (n = 41) using the five-factor model of personality (FFM). The dimensions of the FFM-Neuroticism (N), Extraversion (E), Openness (O), Agreeableness (A), and Conscientiousness (C)-were measured with composite scores derived from the NEO Personality Inventory (NEO PI) and the Revised NEO Personality Inventory (NEO PI-R). While no group differences emerged on N or C, the bipolar patients scored significantly higher on the Positive Emotion facet (subscale) of E than the unipolar patients. The schizophrenic patients scored lower on the Feelings, Values and Actions facets of O than did the unipolar and bipolar patients. The unipolar patients scored higher on A than the schizophrenic patients.

Adult↗
PubMed1997

Increased G alpha q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder.

As disturbances in guanine nucleotide binding (G) protein-coupled phosphoinositide second messenger systems have been implicated in bipolar disorder, we examined whether the abundance of G alpha q/11 and phospholipase C (PLC)-beta 1 two key transducing proteins in this signaling pathway, are altered in this disorder. Compared with the controls, immunoreactive levels of G alpha q/11 were significantly elevated by 62% (p = .047) in occipital cortex of bipolar subjects. A similar increase (52%) in the PLC-beta 1 immunolabeling was also found in the occipital cortex of the bipolar subjects, but only reached marginal statistical significance (p = .07). In contrast, frontal and temporal cortex G alpha q/11 or PLC-beta 1 immunolabeling did not differ between bipolar and control subjects. Cerebral cortical immunoreactive levels of G beta 1 or G beta 2, included as a negative control, were not different between comparison groups. These findings support and extend earlier observations suggesting that disturbances in G protein-coupled second messenger signaling pathways may play an important role in the pathophysiology of bipolar affective disorder.

Adult↗
PubMed1997

Nitric oxide donor SIN-1 mediated down-regulation of the G-protein alpha-subunit in C6 glioma cells.

In C6 glioma cells, the nitric oxide (NO) donor 3-morpholinosynonimine hydrochloride (SIN-1) (0.5 mM) produced a significant decrease in the stimulatory G-protein alpha subunit (G alpha(s)) levels. Northern hydridization did not detect any differences in G alpha(s) mRNA levels after SIN-1 treatment. Furthermore SIN-1 increased endogenous and cholera toxin-catalyzed ADP-ribosylation of G alpha(s). 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) (0.5mM), a NO scavenger, had no effect on endogenous or cholera toxin-catalyzed ADP-ribosylation of G alpha(s), but reversed the increase in endogenous and cholera toxin-catalyzed ADP-ribosylation of G alpha(s) induced by SIN-1. These results suggest that increasing ADP-ribosylation may be involved in SIN-1 mediated G alpha(s) down-regulation.

Adenosine Diphosphate Ribose↗
PubMed1997

Levels of functioning and well-being in recovered psychotic versus nonpsychotic mania.

The aim of the study was to compare psychotic and nonpsychotic bipolar patients on demographic and outcome measures. Sixty two patients with bipolar disorder were divided into groups on the basis of psychosis during an index episode of mania. Groups were compared on demographic, clinical and outcome measures. Psychotic patients were more symptomatic during the index episode, but they did not differ from nonpsychotic patients on ratings of function and well being when euthymic. Psychosis occurring within the context of an exacerbation of mania does not seem to predict a poorer outcome when patients return to the euthymic state. A limitation of the present study is that it involves short-term outcome, but the data can be used to inform patients and family about the possibility of full recovery even in the psychotic form of mania.

Adult↗
PubMed1997

Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder.

Findings of increased Gs alpha levels and forskolin-stimulated adenylyl cyclase activity in selective cerebral cortical postmortem brain regions in bipolar affective disorder (BD) implicate increased cyclic AMP (cAMP)-mediated signaling in this illness. Accumulating evidence suggests that intracellular levels of cAMP modulate the abundance and disposition of the regulatory subunits of cAMP-dependent protein kinase (cAMP-dPK). Thus, in the present study, we tested further whether hyperfunctional Gs alpha-linked cAMP signaling occurs in BD by determining [3H]cAMP binding, a measure of the levels of regulatory subunits of cAMP-dPK, in cytosolic and membrane fractions from discrete brain regions of postmortem BD brain. Specific [3H]cAMP (5 nM) binding was determined in autopsied brain obtained from 10 patients with DSM-III-R diagnoses of BD compared with age- and postmortem delay-matched controls. [3H]cAMP binding was significantly reduced across all brain regions in cytosolic fractions of BD frontal (-22%), temporal (-23%), occipital (-22%) and parietal (-15%) cortex, cerebellum (-36%), and thalamus (-13%) compared with controls, but there were no differences in [3H]cAMP binding in the membrane fractions from these same regions. These results suggest that changes occur in the cAMP-dPK regulatory subunits in BD brain, possibly resulting from increased cAMP signaling. The possibility that antemortem lithium and/or other mood stabilizer treatment may contribute to the above changes, however, cannot be ruled out.

Adult↗
PubMed1997

Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness.

In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.

Adult↗