Preclinical Psychopharmacology and Neurobiology
Antidepressant and ECS effects on 5-HT1A and 5-HT1B receptor functioning in vivo
Investigators: M. Newman, E. Gur, B. Lerer
This project studies the effects of antidepressant drugs and electroconvulsive shock (ECS) as a model for electroconvulsive therapy (ECT) in patients, on serotonin 5-HT1A receptors situated both presynaptically and postsynaptically and 5-HT1B receptors located presynaptically in the rat brain. Presynaptic receptor activity is studied using in vivo microdialysis to measure 5-HT levels, while postsynaptic receptor activity is studied in the hippocampus by measurement of cyclic AMP levels and in the hypothalamus by means of hormone measurements performed ex vivo.
MRI scan of rat brain after microdialysis procedure.
Effects of repetitive transcranial magnetic stimulation (rTMS) on 5-HT1A and 5-HT1B receptor functioning in vivo
Investigators: E. Gur, M. Newman, B. Lerer
This project studies the effects of rTMS on serotonin 5-HT1A receptors situated both presynaptically and postsynaptically and 5-HT1B receptors located presynaptically in the rat brain. Presynaptic receptor activity is studied using in vivo microdialysis to measure 5-HT levels, while postsynaptic receptor activity is studied in the hippocampus by measurement of cyclic AMP levels and in the hypothalamus by means of hormone measurements performed ex vivo.
Mechanism of action of triiodothyronine as an augmenting agent in the treatment of depression
Investigators: M. E. Newman, E. Gur, B. Lerer
In this project we propose to study the effects of the thyroid hormone, triiodothyronine or T3, on serotonergic function in the rat brain. T3 is extensively used as an augmenting agent in the treatment of depressed patients who have failed to respond to an antidepressant drug given alone. Indeed addition of T3 to a treatment regimen constitutes one of the steps in the algorithm-based pharmacological treatment of depression developed in our department (see Research Projects: Clinical Psychopharmacology and Neurobiology). Preliminary results have shown that administration of T3 to rats for 7 days resulted in increased 5-HT levels and subsensitivity of presynaptic 5-HT1A receptor acticvity in the cortex. This effect was more pronounced when T3 was administered together with the tricyclic antidepresssant clomipramine. In future work we will extend these findings by determining the time course and dose-dependence of the T3 effect, thus providing a rational basis for its use in the clinic.
Role of serotonin in control of release of hypothalamic hormones
Investigators: M. E. Newman (with S. Feldman and J. Weidenfeld, Department of Neurology, Hadassah)
This project has focussed in particular on the role of the amygdala in controlling hormone release from the hypothalamus in rats. Depletion of serotonin in the amygdala by injection of the specific serotonergic neurotoxin 5,7-dihydroxytryptamine resulted in inhibition of the activity of the hypothalamic-pituitary-adrenocortical axis. Similarly, injection of specific serotonergic or adrenergic agonists into the amygdala induced hormone release from the hypothalamus.
Effects of antidepressant drugs on lipopolysaccharide-induced serotonin release
Investigators: M.E. Newman, E. Gur (with R. Yirmiya, Dept. of Psychology, Hebrew University)
Lipopolysaccharide (LPS) or bacterial endotoxin can be used as a form of immune challenge similar to that encountered in human infectious diseases. LPS is known to activate the brain serotonergic system, and in these experiments it induced an increase in serotonin release in hippocampus and hypothalamus as measured by in vivo microdialysis. Administration of the tricyclic antidepressant drug clomipramine abolished the LPS effect in the hypothalamus, suggesting a role for the immune system in the action of antidepressant drugs.
Effects of food restriction on brain 5-HT levels in female rats, in relation to anorexia nervosa
Investigators: E. Gur, M.E. Newman (with E. Berry, Dept. of Nutrition, Hebrew University School of Medicine)
Serotonin has been shown to be involved in control of feeding behavior in experimental animals, and by implication in human eating disorders such as anorexia nervosa and bulimia. Using in vivo microdialysis in female rats, we have shown that partial food deprivation for 4 weeks results in subsensitivity of presynaptic 5-HT-1B autoreceptors in the hypothalamus. This effect, which leads to increased serotonergic neurotransmission in this brain area, may be an adaptive response to the food deprivation.
Neurobiology and neurochemistry of early separation
Investigators: B. Lerer, J Adelman, M.E. Newman, E. Gur (with J. Yanai, Dept of Anatomy, Hebrew University School of Medicine)
As well as a strong genetic component, the incidence of depression is heavily influenced by environmental factors. Early parental loss is one of these factors. We have mimicked this in experimental animals by temporarily separating newly-born rats from their mothers for various periods. At maturity the rats will be examined for changes in serotonergic neurotransmission in the brain, using in vivo microdialysis. Until now studies examining the effects of separation in animals have concentrated on the hypothalamo-pituitary-adrenal axis, and the present study promises to provide neurobiological data to complement these findings.
