Ora Kofman

The role of prenatal stress in the etiology of developmental behavioural disorders

Substantial evidence from preclinical laboratory studies indicates that prenatal stress (PS) affects the hormonal and behavioural development of offspring. In the following review, the effects of PS in rodents and non-human primates on hypothalamic-pituitary-adrenal (HPA) reactivity to stress, morphological changes in the brain, motor behaviour and learning are surveyed. PS has been found to alter baseline and stress-induced responsivity of the HPA axis and levels and distribution of regulatory neurotransmitters, such as norepinepherine, dopamine, serotonin and acetylcholine and to modify key limbic structures. In rodents and non-human primates, PS affected learning, anxiety and social behaviour. The relevance of these findings to humans is discussed with respect to (a) the effect of administration of exogenous corticosteroids in pregnancy and (b) maternal state and trait anxiety during gestation and its relation to foetal autonomic regulation as putative predisposing factors in the pathogenesis of behavioural developmental delays in children.

Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression

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 Lis therapeutic action and that design of new inositol monophosphatase inhibitors may be a practical strategy to create new compounds with Li-like therapeutic effects.

Inositol treatment raises CSF inositol levels.

Inositol is a key precursor for synthesis of phosphatidylinositol in a major second messenger signalling system. It is biologically active in syndromes such as respiratory distress syndrome but has been thought to be excluded from CNS by the blood-brain barrier. Oral inositol treatment of 8 patients is shown to significantly increase CSF inositol by almost 70%, suggesting possible CNS therapeutic applications of this compound and possible CNS side-effects of systemic therapy.

Restoration of brain myo-inositol levels in rats increases latency to lithium-pilocarpine seizures.

Lithium pretreatment in rats potentiates the epileptogenic effects of pilocarpine and other cholinergic agonists. In order to determine if this effect of lithium could be reversed bymyo-inositol, rats were pretreated with intracerebroventricular (ICV) injections ofmyo-inositol, artificial CSF orl-chiro-inositol. Lithium chloride, 3 meq/kg was administered intraperitoneally 20–24 h prior to the subcutaneous injection of pilocarpine 20 or 30 mg/kg. In both experiments,myo-inositol significantly prolonged the latency to the appearance of clonic seizures and lowered the pilocarpine seizure score.myo-Inositol prevented the development of clonic seizures in 50% of the rats receiving pilocarpine, 20 mg/kg. The levels of corticalmyo-inositol in rats injected withmyo-inositol were approximately double those of the CSF andl-chiro-inositol groups.

Enhanced performance on executive functions associated with examination stress: Evidence from task-switching and Stroop paradigms

Stressful life situations can impair or facilitate various cognitive functions. In the present study, the effect of examination stress on students was examined using two executive function tasks, task-switching and the Stroop task, in a between-subject crossover design. Students showed increased anxiety in the 2 week period prior to exams compared to the beginning of the semester, manifested as higher scores on the Spielberger State-Trait Anxiety Scale and a shift to more sympathetic activation when heart rate variability was assessed. During the stressful period, the switching cost was reduced on a spatial task-switching paradigm and reaction times in the Stroop task were faster. This is the first study to show stress-induced facilitation of performance on these executive function tasks.

Motor inhibition and learning impairments in school-aged children following exposure to organophosphate pesticides in infancy

Despite the critical role of acetylcholinesterase (AChE) in cortical function and development, no long-term studies have been conducted in humans on the long-term sequelae of the disruption of the cholinergic system in early childhood. We report a neuropsychological assessment of healthy school-aged children, who had been hospitalized in infancy following exposure to organophosphate pesticides, compared with children exposed to other toxins such as kerosene, and age- and sex-matched non-exposed children. Although overall, the children seem to have overcome the acute one-time exposure incident, and they all attend regular schools, a finer assessment of specific cognitive abilities indicates they are impaired compared with the matched controls. Specifically, the children who had been exposed to organophosphate pesticides had a deficit in inhibitory motor control. Children with pesticide or kerosene poisoning had a retrieval deficit on the acquisition phase of a verbal learning task.

Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub-threshold pesticide exposure

Organophosphate pesticides (OPs), known inhibitors of acetylcholinesterase (AChE), are used extensively throughout the world. Recent studies have focused on the ACHE/PON1 locus as a determinant of inherited susceptibility to environmental OP exposure. To explore the relationship of the corresponding geneenvironment interactions with brain activity, we integrated neurophysiologic, neuropsychological, biochemical, and genetic methods. Importantly, we found that subthreshold OP exposure leads to discernible physiological consequences that are significantly influenced by inherited factors. Cortical EEG analyses by LORETA revealed significantly decreased theta activity in the hippocampus, parahippocampal regions, and the cingulate cortex, as well as increased beta activity in the prefrontal cortex of exposed individuals—Areas known to play a role in cholinergic‐associated cognitive functions. Through neuropsychological testing, we identified an appreciable deficit in the visual recall in exposed individuals. Other neuropsychological tests revealed no significant differences between exposed and non‐exposed individuals, attesting to the specificity of our findings. Biochemical analyses of blood samples revealed increases in paraoxonase and arylesterase activities and reduced serum acetylcholinesterase activity in chronically exposed individuals. Notably, specific paraoxonase genotypes were found to be associated with these exposure‐related changes in blood enzyme activities and abnormal EEG patterns. Thus, geneenvironment interactions involving the ACHE/PON1 locus may be causally involved in determining the physiological response to OP exposure.—Browne, R. O., Ben Moyal‐Segal, L., Zumsteg, D., David, Y., Kofman, O., Berger, A., Soreq, H., Friedman, A. Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub‐threshold pesticide exposure. FASEB J. 20, E1103–E1113 (2006)

Differential uptake of myo-inositol in vivo into rat brain areas

Oral inositol has been reported to have antidepressant and antipanic properties in humans. Inositol enters the brain poorly and high doses are required. Natural uptake processes and specific transporters are involved. We here report that intraperitoneally administered inositol is taken up differently by various brain areas and that brain areas have different baseline inositol levels. These effects could be important in understanding the differential effects of lithium-induced lowering of inositol and of behavioral effects of exogenous inositol.

INTRACEREBROVENTRICULAR MYO-INOSITOL ANTAGONIZES LITHIUM-INDUCED SUPPRESSION OF REARING BEHAVIOUR IN RATS

Several biological effects of lithium have been reversed by in vitro myo-inositol. To determine if intracerebroventricular myo-inositol would reverse behavioural effects of lithium, rats were injected with 5 meq/kg lithium chloride or sodium chloride and injected intracranially with myo-inositol (10 mg) or artificial CSF 24 h and 15 min prior to measurement of activity in an automated activity monitor. Myo-inositol alone had no significant effect on behaviour, but significantly reversed suppression of rearing activity by lithium.

High-dose peripheral inositol raises brain inositol levels and reverses behavioral effects of inositol depletion by lithium

Lithium (Li) reduces brain inositol levels. Berridge has suggested that this effect is related to Lis mechanism of action. It had previously been shown that pilocarpine causes a limbic seizure syndrome in lithium treated rats, and that these lithium-pilocarpine seizures are reversible by intracerebroventricular inositol administration to rats. We now show that although inositol passes the blood-brain barrier poorly, large doses of intraperitoneal (IP) inositol can also reverse Li-pilocarpine seizures. Using gas chromatography, IP inositol can raise brain inositol levels. Demonstration that inositol enters brain after peripheral administration provides a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle.