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Biomedical subjects

R H Belmaker

Publications and source records attributed to R H Belmaker.

At least 91 records · Page 5Linked to original sources
PubMed1999

Rat brain monoamines after acute and chronic myo-inositol treatment.

Inositol was reported to have effects in depression, panic disorder and OCD, and in animal models of depression and anxiety. The present study tested whether inositol treatment alters monoamine systems. Brain areas of rats pre-treated with acute or chronic inositol were analysed by HPLC for monoamines and their metabolites and compared to control animals. Inositol treatment had no significant effect on levels of monoamines, their metabolites, or turnover rates compared to controls.

Administration, Oral↗
PubMed1999

Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants.

We and others have previously shown that the dopamine D4 exon III repeat (D4DR) and the serotonin-transporter promoter region (5-HTTLPR) polymorphisms are not only associated with adult personality traits1-7 but also with temperament in 2-week-old neonates.8 We now report the results of a second study of these infants and their temperament at 2 months using Rothbart's Infant Behavior Questionnaire (IBQ).9 There were significant negative correlations between neonatal orientation and motor organization as measured by the Neonatal Behavioral Assessment Scale (NBAS)10 at 2 weeks and negative emotionality, especially distress in daily situations, at 2 months of age. There were significant main effects for negative emotionality and distress when the infants were grouped by the D4DR and the 5-HTTLPR polymorphisms. Infants with long D4DR alleles had significantly lower scores on Negative Emotionality (F[1, 72] = 8.50, P = 0.005) and Distress to Limitations (F[1,72] = 4.93, P = 0.03) than infants with short D4DR alleles. In contrast, infants with the short homozygous (s/s) 5-HTTLPR genotype had higher scores on Negative Emotionality (F[1,72] = 3.88, P = 0.053) and Distress to Limitations (F[1,72] = 4.94, P = 0.029) than infants with the I/s or I/I genotypes. The strongest effects occurred in those infants with the s/s 5-HTTLPR polymorphism who also were lacking long D4DR alleles which in some studies has been linked to adult novelty seeking.1,6 These infants showed most negative emotionality and most distress to daily situations, temperament traits that are perhaps the underpinning of adult neuroticism.

Adult↗
PubMed1999

Psychological responses in family members after the Hebron massacre.

The authors attempted to determine the frequency of severe psychological responses in surviving family members in a religious Muslim culture. Twenty-three wives, twelve daughters and twenty-six sons of heads of households massacred while praying in the Hebron mosque on 25 February 1994 were interviewed with the clinician-administered PTSD scale; 50% of daughters, 39% of wives, and 23% of sons met criteria for PTSD. PTSD or traumatic bereavement occurs with high frequency after a major tragedy in a Moslem society, despite religious admiration of dead martyrs.

Adaptation, Psychological↗
PubMed1998

Cerebrospinal fluid inositol monophosphatase: elevated activity in depression and neuroleptic-treated schizophrenia.

BACKGROUND: Inositol monophosphatase (IMPase) is a key enzyme in the regulation of the activity of the phosphatidyl inositol (PI) signaling pathway. This enzyme is also found in the cerebrospinal fluid (CSF), where it may prove useful as a marker of dysfunctional PI signal transduction. METHODS: IMPase activity was measured in lumbar CSF of depressed and neuroleptic-treated schizophrenic patients. In addition, and to gain an insight into the factors that influence the levels of CSF IMPase, enzyme activity was measured in subgroups of schizophrenic patients treated for 3-7 days with lithium or 7 days with inositol. RESULTS: CSF IMPase activity was significantly increased by 88% in depressed and by 172% in schizophrenic patients relative to control subjects. Lithium produced a marked increase in CSF IMPase activity in the group as a whole, and this group effect could be more specifically attributed to 3 of the 8 individuals in whom enzyme activity increased by over 300%. On the other hand, inositol had no effect on CSF IMPase activity. CONCLUSIONS: In the absence of a clear relationship between CSF IMPase activity and neuronal PI signaling pathways it is not possible to correlate these changes with altered neuronal function. Nevertheless, increased CSF IMPase activity in depression and schizophrenia may be a marker of the pathophysiological processes underlying these disorders. Moreover, the large lithium-induced increase in IMPase activity seen in a subgroup of schizophrenic subjects suggests a differential regulation of CSF enzyme activity in these patients.

Antipsychotic Agents↗
PubMed1998

Inositol levels are decreased in postmortem brain of schizophrenic patients.

BACKGROUND: A previous study reported decreased levels of inositol in frontal cortex of postmortem brain from bipolar patients and suicide victims. The aim of the present study was to test the specificity of this finding. METHODS: Inositol and the enzyme that synthesizes it, inositol monophosphatase, were measured in postmortem brain tissue from frontal and occipital cortex and cerebellum from 10 schizophrenic patients and the previously reported controls. Inositol levels were assayed gas-chromatographically as trimethylsilyl derivatives with mannitol as an internal standard. Inositol monophosphatase activity in brain homogenates was measured as the difference between phosphate release from inositol-l-phosphate in the absence and in the presence of Li+. RESULTS: Inositol was significantly reduced in all three areas in the schizophrenic patient' brains: inositol monophosphatase was unchanged. Postmortem interval did not correlate with inositol levels and did not differ between control group and schizophrenic patients. CONCLUSIONS: These results suggest an abnormality of second messenger precursor availability in common with schizophrenia and affective psychopathology.

Aged↗
PubMed1998

Chronic treatment with lithium and pretreatment with excess inositol reduce inositol pool size in astrocytes by different mechanisms.

Chronic treatment with a lithium salt is the classical treatment for manic-depressive disorder. It is hypothesized that the therapeutic action of lithium is caused by its inhibition of inositol phosphatases which leads to a relative deficiency of inositol and, therefore, an impairment of inositol recycling and production of precursor for the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). However, peculiarly enough, treatment with high doses of inositol also has an antidepressant effect. In the present work, we have studied the acute and chronic effects of lithium and of excess inositol, in separation or together, on accumulation of 50 microM [3H]inositol (a physiologically relevant concentration) into primary cultures of mouse astrocytes. Two parameters were investigated: (1) rate of unidirectional uptake across the cell membrane (measured during short-term exposure to the radioisotope), and (2) magnitude of the intracellular pool of inositol, equilibrating with extracellular inositol (measured during long-term exposure to the radioisotope). Inositol uptake was highly concentrative and occurred with a Km of approximately 500 microM and a Vmax of 1.5 nmol/min/mg protein. The uptake rate was not affected by either acute or chronic treatment with LiCl (or both), but it was substantially reduced ('down-regulated') after pretreatment with a high concentration of inositol. The inositol pool size was decreased to a similar extent as the uptake rate by previous exposure to excess inositol. In spite of the fact that inositol uptake rate was unaffected by lithium, the magnitude of the inositol pool was significantly decreased by chronic treatment with a pharmacologically relevant concentration of LiCl (1 mM), but not by treatment with lower concentrations. This decrease is likely to reflect a reduction in either inositol synthesis or replenishment of inositol from IP3, due to the inhibition of inositol phosphatases by the lithium ion. In agreement with the different mechanisms by which lithium and pretreatment with excess inositol appear to reduce the pool size of inositol, the effects of pretreatment with excess inositol and of LiCl were additive. It is noteworthy that both effects could be observed in astrocytes, suggesting that there might be a significant astrocytic target during clinical treatment.

Animals↗
PubMed1998

Augmentation of lithium's behavioral effect by inositol uptake inhibitors.

Lithium inhibits the enzyme inositol monophosphatase and thus obstructs the enzymatic degradation of inositol triphosphate (IP3) to inositol in the phosphate-phosphoinositide (PIP) cycle. This inhibition may result in reduced availability of the second messengers IP3 and DAG that are derivates of the PIP cycle, and this action is currently a leading hypothesis regarding lithium's therapeutic and prophylactic effect in affective disorders. Inositol is also available to the cell by uptake from the intercellular matrix, and therefore it is possible that compounds that block the uptake may have lithium-like effects. To test this hypothesis, the present study evaluates the effects of two inositol uptake inhibitors, the carbohydrate L-fucose and the cyclodepsipeptide nordidemnin, in a behavioral model of pilocarpine-induced seizures known to be enhanced by lithium. We tested the possibility that L-fucose produces lithium-like effects, or that L-fucose or nordidemnin augment lithium's behavioral effects. Results indicate that acute ICV treatment with L-fucose did not by itself have a lithium-like effect in the behavioral model, but significantly augmented lithium's effect when combined with lithium treatment. Nordidemnin treatment showed similar effects. The results suggest that when inositol monophosphatase is inhibited by lithium, further restriction of cellular inositol availability may result in an augmentation of lithium's behavioral effects. It is possible that such manipulations may be applicable in the treatment of patients with affective disorders, especially patients who are poor responders to lithium monotherapy.

Animals↗
PubMed1998

Effect of inositol treatment on the behavior of rhesus monkeys: preliminary results.

1. The effects of inositol (20 g/day, oral) on spatial learning and spontaneous home-cage behavior of four Rhesus monkeys, were studied in a crossover design. 2. Results indicate no marked inositol effect on learning, memory, or behavior. There was a suggestion of an effect of chronic inositol in reducing cage-induced repetitive behavior as indicated by increased switching between modes of behavior, and reduction in length of longest behavioral about. Furthermore inositol may increase time spent in environmentally- rather than self-oriented behavior. 3. Previous behavioral studies of inositol were performed in rats, which maintain low brain inositol levels compared to primates, including humans. The present study demonstrates the feasibility of primate behavioral studies with inositol, and shows the need for longer time experiments and increased variety of behavioral tests.

Animals↗
PubMed1998

Behavioral reversal of lithium effects by four inositol isomers correlates perfectly with biochemical effects on the PI cycle: depletion by chronic lithium of brain inositol is specific to hypothalamus, and inositol levels may be abnormal in postmortem brain from bipolar patients.

The inositol depletion hypothesis of lithium (Li) action has been criticized, because depletion of inositol after chronic Li treatment has not been reproducible, effects of inositol to reverse Li-induced behaviors occurred also with epi-inositol, a unnatural isomer, and because inositol is ubiquitous in brain and hard to relate to the pathogenesis of affective disorder. Therefore, we review our studies showing that lithium depletion of brain inositol occurs chronically in the hypothalamus, a region not previously examined; that behavioral effects of four different inositol isomers including epi-inositol correlate perfectly with their biochemical effects; and that inositol in postmortem human brain is reduced by 25% in frontal cortex of bipolars and suicides as compared with controls. Because inositol in postmortem brain is reduced and not increased in bipolar patients, the relationship between inositol, lithium, and affective disorder is complex.

Aged↗
PubMed1998

Dopamine D4 receptor and serotonin transporter promoter in the determination of neonatal temperament.

Genetic effects on behavior were evaluated at a time in early development when we hypothesized that environmental influences are minimal and least likely to confound associations between temperament and genes. The behavioral effects of two common polymorphisms linked respectively in some, but not all, studies to novelty seeking (dopamine D4 receptor-D4DR) and neuroticism and harm avoidance (serotonin transporter promoter region-STPR) were examined in a group of 81 two-week-old neonates. Neonate temperament was evaluated using the Brazelton neonatal assessment scale (NBAS). Multivariate tests of significance showed a significant association of D4DR across four behavioral clusters pertinent to temperament including orientation, motor organization, range of state and regulation of state. A significant multivariate interaction was also observed between D4DR and STPR. The effect of the homozygous short STPR genotype (s/s) was to lower the orientation score for the group of neonates lacking the long form (L) of D4DR. When adult subjects were grouped by the STPR polymorphism there is no significant effect of L-D4DR in those subjects homozygous for the STPR short form (s/s) whereas in the group without the homozygous genotype the effect of L-D4DR is significant and accounts for 13% of the variance in novelty seeking scores between groups.

Anxiety↗