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    Ora Kofman

    Two data sets contain the scores for testing reflexes in mouse pups that had been exposed on gestational days 12-15 to chlorpyrifos or (control) oil.<br>Genotypes: PON1 knockout vs PON1 wild typeTreatments: Oil (vehicle),... more
    Two data sets contain the scores for testing reflexes in mouse pups that had been exposed on gestational days 12-15 to chlorpyrifos or (control) oil.<br>Genotypes: PON1 knockout vs PON1 wild typeTreatments: Oil (vehicle), chlorpyrifos 0.5 mg/kgReflex scores: Right reflex (seconds)Negative GeotaxisCliff Avoidance <br>1 data set contains the social preference test score.Ratio of time spent on in the zone containing the mouse vs. other zonesCodes : Social - proximal - SP Social distant - SD Object- proximal -OP Object -Distant - OD<br>SCPP and FCPP data sets refer to change in preference for the initially non-preferred side after conditioning to a social stimulus (SCPP) or food (FCPP)<br>
    Impaired phosphodiesterase (PDE) function and mitochondrial Ca2+ - [Ca2+]m signaling leads to cardiac failure, ischemic damage and dysfunctional learning and memory. Yet, a causative link between these pathways is unknown. Here, we... more
    Impaired phosphodiesterase (PDE) function and mitochondrial Ca2+ - [Ca2+]m signaling leads to cardiac failure, ischemic damage and dysfunctional learning and memory. Yet, a causative link between these pathways is unknown. Here, we fluorescently monitored [Ca2+]m transients in hippocampal neurons evoked by caffeine followed by depolarization. [Ca2+]m efflux was apparent in WT but diminished in neurons deficient in the mitochondrial Na+/Ca2+ exchanger NCLX. Surprisingly, neuronal depolarization-induced Ca2+ transients alone failed to evoke strong [Ca2+]m efflux in WT neurons. Caffeine is also a PDE inhibitor. Pretreatment with the PDE2 inhibitor Bay 60-7550 rescued [Ca2+]m efflux triggered by neuronal depolarization. Inhibition of PDE2 acted by diminishing the Ca2+ dependent reduction of mitochondrial cAMP, thereby promoting NCLX phosphorylation. Selective PDE2 inhibition also enhanced [Ca2+]m efflux triggered by neuromodulators. We found that protection of neurons against excitotoxi...
    The role of the rare soluble splice variant of acetylcholinesterase (AChE-R) in anxiety behavior was assayed using the elevated plus maze (EPM). The effects of pretreatment with restraint stress and the acetylcholinesterase inhibitor... more
    The role of the rare soluble splice variant of acetylcholinesterase (AChE-R) in anxiety behavior was assayed using the elevated plus maze (EPM). The effects of pretreatment with restraint stress and the acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP) were tested, as these treatments are known to enhance the expression of AChE-R in several brain regions. Mice from the CD-1 outbred and C57BL/6 inbred strains were randomly assigned to seven treatment groups: homecage control, elevated plus maze without pretreatment, 3 days restraint stress or 3 days pretreatment with saline or one of three doses of DFP, for a total of 14 groups. All mice, except homecage controls, were tested twice on the elevated plus maze. AChE-R transcript expression was increased following elevated plus maze stress in hippocampus and amygdala, but not in the prefrontal cortex of CD-1 and not in C57BL/6 mice. Saline-injected C57BL/6 mice had reduced expression of AChE-R transcripts compared to untreated C57 BL/6 mice. DFP pretreatment reversed the stress-induced changes, increased AChE-R transcripts in CD-1 mice. AChE-R expression in the striatum and amygdala were positively correlated with anxiety in the EPM.
    The hypothesis was tested that sedation and stereotyped behaviour, developing in rats after the administration of the steroid derivative with gamma-aminobutyric acid (GABA) antagonistic properties, R 5135, are of an epileptiform nature.... more
    The hypothesis was tested that sedation and stereotyped behaviour, developing in rats after the administration of the steroid derivative with gamma-aminobutyric acid (GABA) antagonistic properties, R 5135, are of an epileptiform nature. Electroencephalographic (EEG) and visual evoked potentials (VEP) were recorded and behaviour was observed over not less than 5-7 hr after subconvulsive doses of R 5135. Doses of 2-4 mg/kg of the compound produced quasi-rhythmic spikes resembling experimental focal epileptic discharges in all rats. This epileptiform activity was accompanied by behavioural sedation and somnolence, followed by a build-up of stereotyped behaviour and sporadic episodes of epileptiform motor activity, developing 1-2 hr after injection. The secondary components (SNW) of the visual evoked potentials were suppressed by R 5135 and the primary potential (N1) facilitated, virtually reducing the visual evoked potential to the form of an evoked spike. Pretreatment with the anticonvulsant GABAergic drugs gamma-acetylenic GABA (GAG) (100 mg/kg), sodium valproate (VPA) (400 mg/kg) and diazepam (5 mg/kg) suppressed the motor components of seizure activity, producing severe ataxia, but not the electrographic manifestation of seizure activity. Neither gamma-acetylenic GABA nor valproate significantly altered the latency to onset of spiking, although all three drugs did significantly reduce the frequency of discharges. Diazepam was the only anticonvulsant tested which completely suppressed spike activity in 3 of 5 rats. Moreover, R 5135 was found to antagonize diazepam, but not valproate induced suppression of secondary components of the visual evoked potential, suggesting that diazepam and R 5135 may compete for the same receptor.
    The therapeutic mechanism of the action of lithium in the treatment of bipolar affective disorder is not known, in spite of a burgeoning number of biochemical studies linking lithium to signal transduction processes. This article reviews... more
    The therapeutic mechanism of the action of lithium in the treatment of bipolar affective disorder is not known, in spite of a burgeoning number of biochemical studies linking lithium to signal transduction processes. This article reviews a decade of studies examining the behavioural manifestations of manipulating inositol, cyclic adenosine monophosphate (cAMP) and G proteins in rats. Inositol, forskolin, dibutyryl cAMP and pertussis toxin all interacted with lithium when rearing behavior was measured. Lithium potentiated the increase in locomotion induced by injections of cholera toxin into the nucleus accumbens, consistent with the hypothesis that it inactivates inhibitory G proteins. More specific interactions were found between lithium and inositol following cholinergic and serotonergic stimulation. Inositol, but not forskolin, attenuated lithium-pilocarpine seizures and the enhancement of the serotonin syndrome; however, inositol had no effect on lithium-induced attenuation of wet dog shakes following an injection of 5-hydroxytryptophan. Behavioural evidence supports biochemical findings suggesting that lithium's interactions with the phoshphatidyl inositol and cyclic AMP signal transduction systems may be relevant to its therapeutic effects in bipolar disorder. Further research on more specific behaviours may elucidate the relevant pharmacological mechanisms underlying the therapeutic effect of lithium.
    This qualitative research focused on the significance of subjective experience of mothers who gave birth in an emergency Caesarean section. Ten first-time mothers experiencing emergency Caesarean section were interviewed, and their... more
    This qualitative research focused on the significance of subjective experience of mothers who gave birth in an emergency Caesarean section. Ten first-time mothers experiencing emergency Caesarean section were interviewed, and their narrative accounts were analyzed using Giorgi's phenomenological method. Mothers described alienation from the infant on encountering her/him; primal difficulties in holding; a 'mechanistic' pattern of childcare at home; over-apprehension and fear of a cradle-death. A few of the women seemed to cope with these experiences by performing 'a symbolic adoption' of their infants. In the context of object-relations theory, the findings, will potentially inform psychological care in obstetrics and gynaecology.
    Children with attention deficit hyperactivity disorder (ADHD) often show poor performance on tasks that require strategic planning. To assess this ability, we developed a paper and pencil task that required consistent use of a simple... more
    Children with attention deficit hyperactivity disorder (ADHD) often show poor performance on tasks that require strategic planning. To assess this ability, we developed a paper and pencil task that required consistent use of a simple test-taking strategy to maximize the number of points. The visual discrimination task with minimal cognitive demands required children to maximize their gains by responding only to outlined high-point problems and to skip the low-point problems. The task was administered twice, the second time with explicit instructions on how to implement the strategy. Few of the children in the ADHD or control group, ages 8-13 years, were able to discover the strategy on their own, but after explicit instruction 90% of the children in the control group but only 57.5% of children with ADHD used the strategy to maximize points (p < .005). The ADHD group used the strategy less efficiently, despite the fact that they did not differ on the total number of problems completed. The findings suggest that children with ADHD have impaired ability to implement strategic approaches for tasks similar to school assignments. The task can potentially be developed as a diagnostic aid and as a basis for further research assessing strategic planning in ADHD.
    A recent controlled double-blind study of 28 patients treated with 12 gm daily of inositol or placebo revealed significant antidepressant effect for this second messenger precursor. Patients were followed-up by interview and Hamilton... more
    A recent controlled double-blind study of 28 patients treated with 12 gm daily of inositol or placebo revealed significant antidepressant effect for this second messenger precursor. Patients were followed-up by interview and Hamilton Depression Scale 10-12 months after the end of the study. Half of the patients who had responded well to inositol relapsed rapidly after inositol discontinuation whereas none of those who responded to placebo relapsed rapidly after placebo cessation. Klein suggested that true drug responders to tricyclic antidepressants respond slowly and gradually whereas placebo responders improve early in an abrupt fashion. However, in the recent study both inositol and placebo responders improved at similar rates. Hamilton Depression Scale Scores 10-12 months after completion of the study were not significantly different between those who had responded and those who had not responded to inositol or to placebo.
    Lithium (Li) reduces brain inositol levels by inhibiting the enzyme inositol monophosphatase. The enzyme inositol-1-phosphatase was measured in human red blood cells of controls, Li-free bipolar patients, and Li-treated bipolar patients... more
    Lithium (Li) reduces brain inositol levels by inhibiting the enzyme inositol monophosphatase. The enzyme inositol-1-phosphatase was measured in human red blood cells of controls, Li-free bipolar patients, and Li-treated bipolar patients and was found to be reduced by 80% in Li-treated bipolars, thus supporting the concept that chronic Li at therapeutic concentrations inhibits this enzyme. Two behaviors in rats caused by Li, reduction of rearing, and Li-pilocarpine seizures, are reversed by intracerebroventricular replenishment of inositol. The reversal is stereospecific to the naturally occurring myo-inositol; whereas the stereoisomer L-chiro-inositol is ineffective. The reversal is dose-dependent, requiring a dose consistent with known quantities of brain inositol depletion; and is time-dependent, as inositol must be given 1-8 h before stimulation. High-dose peripheral inositol also reverses the limbic seizures induced by Li-pilocarpine, and using gas chromatography was shown to increase brain inositol levels that had been reduced by Li treatment. Low-dose inositol could be shown to reverse a peripheral Li-induced side effect, polyuria/polydipsia, in rats and in patients treated with Li. A higher dose of inositol markedly reduced Hamilton Depression Ratings in 9 of 11 unipolar major depressive disorder patients previously unresponsive to tricyclics, in an open design, but had no effect on chronic schizophrenics in a controlled double-blind randomized crossover trial. A new inositol monophosphatase inhibitor, a fungal product originally discovered as a complement inhibitor, was found to act like Li and lower the seizure threshold for subconvulsant doses of pilocarpine. These data suggest that inositol monophosphatase inhibition is a key mechanism of Li's therapeutic action and that design of new inositol monophosphatase inhibitors may be a practical strategy to create new compounds with Li-like therapeutic effects.
    ABSTRACT
    We have recently shown that valproate (VPA) decreases intracellular concentrations of inositol, like lithium but via a different mechanism, namely by inhibiting myo-inositol-1-phosphate (MIP) synthase. Valnoctamide (VCD) and valrocemide... more
    We have recently shown that valproate (VPA) decreases intracellular concentrations of inositol, like lithium but via a different mechanism, namely by inhibiting myo-inositol-1-phosphate (MIP) synthase. Valnoctamide (VCD) and valrocemide (VGD) are VPA derivatives which are anticonvulsants and have been shown in animal models to be significantly less teratogenic than VPA. We now show that 1 mM of either VCD or VGD drastically inhibits human brain crude homogenate MIP synthase activity. We studied the mechanism of the effect of VCD and found that it reduced the enzyme activity by an apparent competitive mode of inhibition at concentrations within the therapeutic range of VPA(Ki = 0.18 mM). We studied the behavioral effect of VGD and found that both lithium and VGD attenuated amphetamine-induced increase in rearing. These data support clinical study of these VPA-derivatives in bipolar disorder.
    Symptoms of both depression and Post-Traumatic Stress Disorder (PTSD) are prevalent among first-time mothers following birth. However, the direction of the association between the two types of symptoms is unclear. Ninety six first-time... more
    Symptoms of both depression and Post-Traumatic Stress Disorder (PTSD) are prevalent among first-time mothers following birth. However, the direction of the association between the two types of symptoms is unclear. Ninety six first-time mothers giving birth via vaginal delivery (N=38), emergency C-Section (N=27) and planned C-Section (N=21) were assessed for depression and PTSD twice: Six weeks post-partum and six-weeks later. Cross-lagged Structural Equation Modeling (SEM) analyses revealed a prospective effect of depressive symptoms on PTSD symptoms. No moderating factors were identified. A relatively modest sample size and only two assessment waves. An early detection and intervention with symptoms of post-partum depression might also prevent the development of PTSD symptoms.
    Background / Purpose: Postnatal exposure to sub-toxic doses of organophosphate pesticides has been associated with neurobehavioral deficits in humans and animals. In this research, the long-term effects of postnatal administration of a... more
    Background / Purpose: Postnatal exposure to sub-toxic doses of organophosphate pesticides has been associated with neurobehavioral deficits in humans and animals. In this research, the long-term effects of postnatal administration of a sub-toxic dose of an irreversible acetylcholinesterase (AChE) inhibitor diisopropylfluorosphosphate (DFP) was compared in adult BALB/C and C57 mice by using classical Pavlovian fear conditioning. In addition, the role of AChE splice variants in the expression of fear and anxiety behaviors was examined. Main conclusion: DFP pretreatment induced lower expression of AChE-R transcript and an increased level of fear responses during cue fear conditioning in BALB/C males compared to controls. We found no significant effects of AChE-R expression in C57 mice. These differences can be used to model variation of early exposure to organophosphates and the involvement of AChE splice variants in the development of anxiety disorder in humans.
    Acute and chronic lithium treatment reduces levels of brain myo-inositol in rats. Several biological effects of lithium can be reversed in vitro by addition of myo-inositol. The ability of myo-inositol to reverse behavioral effects of... more
    Acute and chronic lithium treatment reduces levels of brain myo-inositol in rats. Several biological effects of lithium can be reversed in vitro by addition of myo-inositol. The ability of myo-inositol to reverse behavioral effects of lithium was tested using chronic inositol administration or acute intracerebroventricular (i.c.v.) injections. Chronic myoinositol elevated activity during the first 10 min in an open field, but did not reverse lithium-induced hypokinesia. Myo-inositol (i.c.v.) reversed the suppression of rearing behavior 24 hrs after an acute dose of lithium (5 mEq/kg) but did not attenuate hypokinesia 24 hrs after a high dose of lithium (10 mEq/kg). Myo-inositol, but not the inactive isomer chiro-inositol (i.c.v.), also significantly prolonged the latency to clonus in the lithium pilocarpine seizure model. These studies suggest that reduction of brain myo-inositol may be a critical mechanism for the behavioral effects of lithium.
    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... more
    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.
    Myo-inositol is an important precursor in cellular second-messenger synthesis. It has been reported to be reduced in the cerebrospinal fluid of depressed patients and to reverse a specific effect of Li on rat behavior when given... more
    Myo-inositol is an important precursor in cellular second-messenger synthesis. It has been reported to be reduced in the cerebrospinal fluid of depressed patients and to reverse a specific effect of Li on rat behavior when given intracerebroventricularly (i.c.v.). However, myo-inositol enters the brain poorly when given peripherally, and its effects on normal rat brain have not been well studied. A series of experiments examined the effect of intraperitoneal inositol in high doses on locomotor activity, on amphetamine-induced hyperactivity, on apomorphine-induced stereotyped behavior, and on pilocarpine-induced behaviors in rats. In addition, the behavioral effect of i.c.v. inositol was compared to that of a control stereoisomer in untreated and lithium-treated rats. Few effects of peripheral myo-inositol were found in these models. However, peripheral inositol in high doses given to rats exhibiting Li-pilocarpine seizures showed that i.p. inositol could prevent these behaviors, con...
    Inositol, a naturally occurring isomer of glucose, is a key intermediate of the phosphatidyl-inositol (PI) cycle, a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. The suggestion that lithium... more
    Inositol, a naturally occurring isomer of glucose, is a key intermediate of the phosphatidyl-inositol (PI) cycle, a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. The suggestion that lithium might treat mania via its reduction of inositol levels led to experiments showing that pharmacological doses of peripheral inositol reverse behavioral effects of lithium in animals and side effects of lithium in man. Cerebrospinal fluid (CSF) levels of inositol are low in depression. An open-label, add-on trial of inositol in depression suggested a beneficial effect. In a subsequent 1-month, parallel-groups, double-blind, placebo-controlled study of 28 patients, inositol was effective as sole therapy for depression (p = .043). Inositol was also effective for panic disorder in a double-blind, random-assignment, placebo-controlled crossover study of 21 patients, with 4 weeks in each phase (p = .02); the effect was comparable to that of imipramine in ...
    The ability to judge the passage of time is critical to behavioral regulation and planning and can be impaired among individuals with attention deficit. Time estimation was tested in young adults screened for attention deficit, based on... more
    The ability to judge the passage of time is critical to behavioral regulation and planning and can be impaired among individuals with attention deficit. Time estimation was tested in young adults screened for attention deficit, based on scores of a self-report questionnaire for attention problems (CAARS), using a prospective reproduction paradigm. Four time intervals (3, 6, 12, and 24 s) were tested in two conditions: (1) reproduction of the duration of a visual stimulus and (2) reproduction of an empty time interval. A significant interaction between gender and group was found suggesting that males, but not females, with attention deficits made larger errors than controls. Males with attention deficits and both groups of females made larger underestimations of time judgement than control males.
    We have recently shown that valproate (VPA) decreases intracellular concentrations of inositol, like lithium but via a different mechanism, namely by inhibiting myo-inositol-1-phosphate (MIP) synthase. Valnoctamide (VCD) and valrocemide... more
    We have recently shown that valproate (VPA) decreases intracellular concentrations of inositol, like lithium but via a different mechanism, namely by inhibiting myo-inositol-1-phosphate (MIP) synthase. Valnoctamide (VCD) and valrocemide (VGD) are VPA derivatives which are anticonvulsants and have been shown in animal models to be significantly less teratogenic than VPA. We now show that 1 mM of either VCD or VGD drastically inhibits human brain crude homogenate MIP synthase activity. We studied the mechanism of the effect of VCD and found that it reduced the enzyme activity by an apparent competitive mode of inhibition at concentrations within the therapeutic range of VPA(Ki = 0.18 mM). We studied the behavioral effect of VGD and found that both lithium and VGD attenuated amphetamine-induced increase in rearing. These data support clinical study of these VPA-derivatives in bipolar disorder.
    Despite research regarding emotional processing, it is still unclear whether fear-evoking stimuli are processed when they are irrelevant and when attention is oriented elsewhere. In this study, 63 healthy university students with high... more
    Despite research regarding emotional processing, it is still unclear whether fear-evoking stimuli are processed when they are irrelevant and when attention is oriented elsewhere. In this study, 63 healthy university students with high fear from snakes or spiders participated in two different experiments. In an emotional modification of the spatial cueing task, 31 subjects (5 males) were asked to detect a target letter while ignoring a neutral or fear-related distracting picture. The distribution of attention was independently manipulated by a spatial cue that preceded the appearance of the picture and the target letter. In an emotional modification of the cognitive load paradigm, 32 subjects (4 males) were asked to discriminate between two target letters, while ignoring a central neutral or fear-related picture, and additional 1, 3, or 5 distracting letters that created a varied attentional load. Fear-related pictures interfered with the performance of highly fearful participants, e...
    The long-term effects of postnatal exposure to an organophosphate substance diisopropylfluorophosphate (DFP) were examined on fear conditioning in adult mice. Immediate and long-term changes in the expression of synaptic... more
    The long-term effects of postnatal exposure to an organophosphate substance diisopropylfluorophosphate (DFP) were examined on fear conditioning in adult mice. Immediate and long-term changes in the expression of synaptic acetylcholinesterase (AChE-S) and readthrough acetylcholinesterase (AChE-R) transcripts were explored, in view of reports relating expression of these splice variants to stress and anxiety. BALB/c and C57BL/6 mice were injected daily, on postnatal days 4-10, with 1 mg/kg of DFP or saline and tested as adults for cued and contextual freezing and scanning. Real-time PCR was used to investigate expression of the rare AChE-R and AChE-S mRNA postnatally and in fear-conditioned adults. DFP-pretreated male mice showed increased conditioned cued scanning and both male and female DFP-treated mice showed enhanced contextual scanning. DFP abolished the stress-induced increase in AChE transcript expression in BALB/c but not in C57BL/6 mice. A significant correlation was found b...
    To investigate the protective role of sense of coherence (SOC) and perceived social support in the effect of emergency/elective caesarian section on post-natal psychological symptoms and impairment in mother-infant bonding. Thirty-seven... more
    To investigate the protective role of sense of coherence (SOC) and perceived social support in the effect of emergency/elective caesarian section on post-natal psychological symptoms and impairment in mother-infant bonding. Thirty-seven women delivering via an emergency C-section, 21 via elective C-section and 38 through a vaginal delivery were assessed six weeks post-partum (Time 1) as to their post-traumatic stress disorder (PTSD) and depressive symptoms, impairment in bonding and SOC and social support. Symptoms and bonding difficulties were assessed again six weeks later (Time 2). Main and interactive effects of mode of delivery and the protective factors were examined. Post-natal depressive and PTSD symptoms and mother-infant bonding. An emergency C-section mode of delivery predicted an increase in PTSD symptoms in Time 2, but only among women with low levels of Time-1 social support. Time-1 SOC predicted a decrease in post-natal PTSD and depression. Social support might buffer...

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