Biomedical subjects

B Dubrovsky

Publications and source records attributed to B Dubrovsky.

At least 19 recordsLinked to original sources

PubMed2006

A paracrine component of salient symptoms of depression in Cushing's of diencephalic origin, and in perimenstrual syndromes: a hypothesis.

Interrelationships between adrenocortical secretions and depression syndromes have been known since early in the 20th century. Now, the fact that pregnane and pregnene steroids are also known to be synthesized in the brain (they are termed neurosteroids (NS)), raises the possibility that these natural compounds could have paracrine effects. Adrenocorticotropic hormone (ACTH) can modulate biosynthesis of NSs. 17beta estradiol has been shown to decrease THP concentration in the brain. It is hypothesized that imbalance between stimulatory and depressant NSs induced by ACTH elevation in hypothalamo pituitary dependent Cushing's, and by estrogen concentration changes during the menstrual cycle, may be associated with the pathophysiology of salient symptoms of depression in Cushing's and in perimenstrual syndromes.

Adrenocorticotropic Hormone↗

PubMed2005

Mechanisms involved in the neural construction of a body-centered reference axis for extrapersonal directed movements. A hypothesis.

To localize objects in space, it is necessary to refer them to a set of coordinates that serve as a frame of reference. Advances in molecular aspects of evolutionary developmental biology reveal how axial coordinates are established in embryos. But we do not yet know how axes of reference are constructed by adult animals. The characteristics of epaxial musculature, spinal connectivity, and organization at the cortical level are reviewed. Although endowed with muscle spindles, epaxial muscles lack the monosynaptic but possess the tonic component of the stretch reflex. Motoneurons of epaxial muscles are devoid of recurrent inhibition and do not show crossed disynaptic inhibition. At motorsensory cortex (MSC), regions corresponding to the body axis receive somatosensory signals that always extend across the midline. Visual and vestibular input also converge in the zone corresponding to the body axis. This region is also endowed with a large number of callosal fibers that, by connecting the two halves of the body axis, may allow them to function and behave as a unity. In contrast, somatic signals from distal extremities are discrete, confined only to the contralateral MSC, and show short latency of responses. They do not receive either telereceptive or vestibular input. We propose that limb movements directed to extrapersonal space take place within a reference frame in which one of the axes is the result of integration at the MSC of telereceptive, proprio and somatosensory signals from the body. Vestibular input signals the effect of the force of gravity, providing directionality to the axis.

Animals↗

PubMed2003

Effects of arginine-vasopressin (AVP) on long-term potentiation in intact anesthetized rats.

We studied the effects of the neuropeptide arginine-vasopressin (AVP) on the long-term potentiation (LTP) paradigm in the dentate gyrus (DG) of urethane intact anesthetized rats. Intracerebroventricular injection of 1 microg of the hormone in 1 microl of physiological solution 3 min before tetanization, produced a significant increase in both components of the perforant path-evoked potentials (EP) in the DG. The effects were already evident 1 min after tetanization. Amplitude of the EPs increased continuously for the 2h of recording time, reaching values 100% above baseline, reference levels. In contrast, in previous in vitro studies, enhancement of LTP with AVP appeared only after 15 min of exposure of the hippocampal slice to the hormone, increased EPSPs were no higher than 50% from baseline, reached a plateau at 40 min decreasing slowly thereafter. Not only quantitative but also qualitative differences can be observed between in vitro and in vivo intact preparations in response to identical hormones. This study emphasizes the importance of hormone neurotransmitter interactions in determining electrophysiological characteristics of response to AVP.

Action Potentials↗

PubMed2002

Oxytocin induces long-term depression on the rat dentate gyrus: possible ATPase and ectoprotein kinase mediation.

We studied the effects of the neuropeptide oxytocin (OT) on the long-term potentiation (LTP) paradigm in the dentate gyrus (DG) of urethane anesthetized rats. Intracerebroventricular injection of 1 microg of the hormone in 1 microl of physiological solution 2min before tetanization produced a significant decrease in both components of the perforant path evoked potentials (EP) in the DG. The effects appeared right after the tetanization stimuli and were more pronounced in the excitatory postsynaptic components of the EPs. The decrements lasted for the 2h of recording time. We concluded that OT induced and maintained long-term depression on the DG. In contrast, injection of OT in the absence of tetanic stimulation did not significantly affect perforant path EP in the DG. The results are discussed taking particular consideration of the inhibitory effects the OT has on (Ca(2+)+Mg(2+)) ATPase at membrane levels and the potential interference that this action may have with phosphorylation processes via an ectoprotein kinase isolated from membranes of hippocampal pyramidal neurons. Blocking of this ectoprotein kinase in vitro significantly impairs establishment and maintenance of LTP.

Action Potentials↗

PubMed2002

Effects of androstenedione on long term potentiation in the rat dentate gyrus. Relevance for affective and degenerative diseases.

We studied the effects of the androgenic hormone androstenedione, a 17-ketosteroid, on long term potentiation (LTP) in the dentate gyrus (DG) of intact, urethane anesthetized rats. Intravenous injection of 10mg of the hormone dissolved in Nutralipid produced a significant increase of the population spike (PS), but not of the excitatory post-synaptic potentials (EPSPs). The results are discussed in terms of the potential enhancement that androstenedione may have on some aspects of memory processes as reported for other androgenic steroids. Also noted are the plausible beneficial effects of the hormone on depression as well as in recovery following both central and peripheral neural injury.

Action Potentials↗

PubMed2001

Dynamics of neural networks: a proposed mechanism to account for changes in clinical symptomatology through time in patients with psychotic diseases.

The classical Kraepelinean dichotomy between manic depressive insanity and the schizophrenias has been recently challenged from clinical and neurobiological quarters. It is not so infrequent to see patients shift from a manic to a schizophrenic symptomatology and vice versa. This paper proposes neurobiological mechanisms as to how these changes may occur, based on recent data on the functioning of neural networks at different modes.

Humans↗

PubMed2000

Androsterone sulfate increases dentate gyrus population spike amplitude following tetanic stimulation.

We studied the effects of the androgenic hormone, androsterone sulfate, a 17-ketosteroid, on long term potentiation in the dentate gyrus (DG) of urethane anesthesized rats. Intravenous injection of 10 mg of the hormone dissolved in Nutralipid produced a significant increase of the population spike (PS), but not of the excitatory post-synaptic potentials (EPSP). The results are discussed in terms of the potential enhancement that androsterone sulfate may have on memory as was described for one of its parent compounds, dehydroepiandrosterone (DHEA) and its potential use as an antidepressant.

Androsterone↗

PubMed2000

Dehydroepiandrosterone sulfate (DHEAS) counteracts decremental effects of corticosterone on dentate gyrus LTP. Implications for depression.

It is well-established that levels of corticosterone sufficient to occupy Type II glucocorticoid receptors produce a decrement in long-term potentiation (LTP) in the dentate gyrus of the hippocampus in rats. In the present series of experiments we investigate the interaction of corticosterone and the neurosteroid dehydroepiandrosterone sulfate (DHEAS) on LTP in the rat dentate gyrus. In confirmation of previous studies, we found that corticosterone (2 mg/kg) had decremental effects on LTP. However, simultaneous injection of corticosterone and DHEAS (30 mg/kg) elicited excitatory post-synaptic potentials and population spikes that were not significantly different from those observed in control animals. The results are discussed in terms of the interaction of the two hormones, the agonist effects of DHEAS on sigma receptors, and their relation with the antidepressant effects of DHEA.

Action Potentials↗

PubMed2000

The specificity of stress responses to different nocuous stimuli: neurosteroids and depression.

The role that adrenal cortex and neurosteroid hormones may have in the etiology and/or maintenance of depressive diseases is discussed. Selye's concept of stress as the summation of unspecific body responses of the autonomic central nervous system (CNS) and hypothalamic pituitary adrenal axis (HPAA) as the main characteristic of it is contrasted with Mason's view of stress responses as being specific for different stimuli, i.e., the neuroendocrine system responds with the production of a hormonal profile individualized and characteristic for the various stimuli applied. The data reviewed provides support for Mason's interpretation of stress as fundamentally a behavioral response. In turn, the high relevance of emotional factors in the determination of stress responses led to a reconsideration of cognitive-affective interactions in nervous systems. Recent results revealed that improvement in depression treated with antidepressants (ADs) is associated with an increase in the neurosteroid 3alpha 5alpha tetrahydroprogesterone, both in the blood and cerebrospinal fluid of recovered patients. The increase occurs with both selective serotonin reuptake inhibitors and tricyclic ADs. An evaluation of the possible and putative roles for neurosteroids in the CNS is presented and suggestions for enhancing the type of supporting data from the laboratory diagnosis of depressions are advanced.

Adrenal Cortex Hormones↗

PubMed1997

Natural steroids counteracting some actions of putative depressogenic steroids on the central nervous system: potential therapeutic benefits.

Psychological similarities in the symptomatology of Cushing's and depressive diseases led to repeated attempts of treatment of the affective disease by suppression of adrenocortical secretion. While successful in many patients, all drugs employed-metyrapone, ketoconazole and aminoglutethimide-carry the danger of inducing adrenal insufficiency. In addition, their undesirable side effects were also a main reason for treatment suspension. In our 1990 proposal for the treatment of depression through control of adrenal steroid levels, we set as one of the goals the identification of steroids which can antagonize each other on their effects on the central nervous system. Specifically, we looked first at steroids that could counter each other's effects on long-term potentiation, a putative memory mechanism in the central nervous system. One reason for this was the consensus that memory mechanisms are affected in both Cushing's and depressive patients. Another was the fact that cortisol-type hormones which underlie, at least in part, the depressogenic actions of adrenal steroids also have inhibitory effects on LTP. We conjectured, then, that a steroid with opposite effects, one that could enhance long-term potentiation and, further, that could counter the depressant effects of corticosterone on long-term potentiation, could be of use in the treatment of depression. Dehydroepiandrosterone sulfate increases long-term potentiation in a dose-related manner, and preliminary data suggest that it also counteracts the depressant effects of corticosterone on long-term potentiation when injected simultaneously on experimental animals. Potentially at least, rather than resort to total suppression of adrenocortical activity, it may be possible to treat depression just by counteracting some of the effects of cortisol-like hormone actions in the central nervous system. Further, both in clinical trials as well as in experimental animals, dehydroepiandro-sterone sulfate has been shown to enhance performance in memory-requiring tasks.

Adrenal Cortex Hormones↗

PubMed1996

Dose-response study of dehydroepiandrosterone sulfate on dentate gyrus long-term potentiation.

Neurosteroids are produced peripherally by endocrine glands, as well as enzymatically in the glia from steroid hormone substrates. GABA receptor sites and Ca2+ channel currents are prime targets for neurosteroid actions, and their effects are concentration dependent. For this reason, and the fact that treatment with one of them, sulfated dehydroepiandrosterone (DHEAS), improves performance in tasks involving memory in aged rats, we explored the effect of this hormone on dentate gyrus long term potentiation (LTP) in a dose-response mode. Intact anesthetized rats (urethane, 1.5 g/kg) were used. Electrodes were stereotaxically positioned in the perforant path and dentate gyrus for stimulation (bifocal) and recording (monofocal). DHEAS (10, 20, and 30 mg/kg, dissolved in Nutralipid 10%) was injected into the femoral vein. Ten animals were used to study the effects of each dose, one injection per animal. Twenty control animals were randomly interspersed within the experimental groups and were injected solely with Nutralipid. The results showed a significant increase in LTP at all doses in relation to baseline values. Further, there were significant increments in amplitude at 20 and 30 mg in relation to 10 mg. However, the data did not reveal significant differences between the 20- and the 30-mg-treated rats. Results are discussed in terms of effects of DHEAS on neurotransmitter and Ca2+ channel ion systems.

Animals↗

PubMed1995

Fundamental neuroscience and the classification of psychiatric disorders.

Non-Darwinian views of evolution of nervous systems (e.g., Jacksonian evolution) conceive the present structure of the human brain as composed of a series of additive layers representing successive phylogenetic stages in evolution, layers which remain static after their emergence. In contrast to this view, recent allometric studies clearly show that limbic structures scale with the growth of the human brain (i.e., they do not remain stable but reach the size expected for the brain of a primate with the weight of a human brain). Data also show that limbic structures are significantly involved in cognitive functions such as memory and attention. Hence overlap of lesions in similar brain loci, especially in limbic regions, in both manic-depression and schizophrenia should come as no surprise. In the psychobiological sphere, the need for cognitive perceptual evaluation of the external world and internal state for emotional experience, further to the necessary visceral arousal, leads to a breakdown of the platonic, essentialist position, emotion vs. cognition at the psychological level, a problematic issue for the Kraepelinean view. Neural networks operation depend upon multiple nonlinear processes at the cellular, synaptic and network levels. Afferent input may serve not only to activate, but also to configure them into one of several circuit modes. These networks have been named polymorphic and can, at least to a measure, account for commonalities in lesion sites, in both affective and schizophrenic diseases. It is proposed that fundamental neuroscience should serve as one of the bases for the classification of psychiatric disorders.

Animals↗

PubMed1993

Effects of adrenocortical steroids on long-term potentiation in the limbic system: basic mechanisms and behavioral consequences.

Hippocampal structures are a major target for adrenal steroid hormones, and hence these neural regions are some of the most likely mediators of the effects of adrenocortical steroids on behavior. Memory disturbance, in particular biasing toward negative contents, are part of the symptomatology presented by depressive patients. In turn, a sizeable subset of depression also presents with hypercortisolemia. Adrenocortical hormones are also known to affect memory processes. Hippocampal formation is essential for declarative memory. We thought it appropriate then to study the effects of adrenal steroids on long-term potentiation, a putative memory mechanism in the hippocampus. Two clearly distinguished components of the evoked response to perforant path stimulation can be studied in the hippocampus: the excitatory postsynaptic potential (EPSP) which denotes the graded depolarization of the somatodendritic region of the neuron and the population spike (PS), a manifestation of the all-or-none-discharge of the cell action potential. Corticosterone had a significant depressant effect on the EPSP component of the evoked response immediately and 15 min after injection. Thereafter EPSP amplitudes were within normal values. Corticosterone significantly decreased the PS immediately after the train, the component remaining low 30 min after the train. 5 alpha-Dihydrocorticosterone (a ring A-reduced metabolite of corticosterone) significantly reduced the PS component of the response at all times after injection. 18-Hydroxydeoxycorticosterone and deoxycorticosterone significantly decreased both EPSP and PS components of the evoked response from the time of infusion. Contrary to expectation, tetrahydrodeoxycorticosterone was ineffective in decreasing and if anything, enhanced the development of long-term potentiation. 18-Hydroxydeoxycorticosterone 21-acetate behaved like vehicle, except for the first 30 min after injection when the EPSP was decreased. Allotetrahydroprogesterone decreased all EPSP's values and had no effect in the PS development in comparison with vehicle. The suggestion is made that the study of steroidal effects on hippocampal LTP can serve as a preclinical model of some aspects of depression in a specific subset of the disease.

Adrenalectomy↗

PubMed1993

A longitudinal CNV study of the evolution and treatment of bipolar illness.

In a longitudinal CNV study of bipolar illness we followed the evolution of this illness in six bipolar patients by recording their CNV and mood changes as well as their psychopharmacological treatment for a period of 8 months. The longitudinal CNV recordings of these patients did not show changes corresponding to their mood variations. The most salient result emerging from this study was the consistency in the patterns of the records in different patients in spite of variations in their clinical state and medications. We believe that these electrophysiological parameters cannot be used as markers of the mental state in bipolar patients nor do they reflect specific drug effect. These findings are congruent with available data which do not support a linear relationship between a complex psychological process such as manic depressive illness and a single physical dimension of brain activity. Further studies are warranted for a deeper understanding of this phenomenon.

Adult↗

PubMed1993

Evolution of nervous systems and psychiatry: consequences of the vertical and horizontal duality of the evolutionary process.

Jacksonian views of brain evolution where new levels "add on" and become higher levels of integration "keeping down" the lower levels are examined. The hierarchical organization is contrasted with modern views of the evolution of nervous systems. These emphasize the "separation or factorization of different aspects of input into distinct processing channels, a factor which appears to be a generalized one in the evolution of brains and a necessary condition to adapt to a varying environment." The advantages of the latter view--vertical and horizontal development--for the interpretation of functional organization of nervous systems are discussed. The view that normal and pathological conditions do not form a continuum, but constitute qualitatively different phenomena, is presented and given support because of recent developments in neuroscience.

Animals↗

PubMed1993

Effects of adrenal cortex hormones on limbic structures: some experimental and clinical correlations related to depression.

Cushing's disorder and depression present overlapping although not identical psychological symptomatology. In turn, a subset of patients with affective disorders present with hypercortisolemia and disturbances, specifically disinhibition, of the hypothalamic hypophysio adrenal axis (HHAA). Memory disturbances, in particular, biasing toward negative contents, overlapping sleep abnormalities (marked reduction of stages 3 and 4) increased fatigue and loss of energy, attentional deficits and irritability, are just part of the common symptomatology presented by patients with both Cushing's disorder and depression. All of these behavioral manifestations are known to be affected by adrenal steroid hormones. There is consensus that hippocampal structures are a main target for adrenal steroid hormones; hence, these neural regions are some of the most likely mediators of the effects of corticoadrenal steroids on behavior. This paper proposes that an imbalance of adrenal steroids and their metabolites may play a fundamental role in the psychophysiopathology of Cushing's and depressive disorders. The imbalance of these hormones, especially at limbic sites, could distort mood and memory content affecting cognition based on recollection and present experiences. Reestablishing an adrenal balance could therefore be considered as a therapeutic aid in a subset of depressive disorders.

Adolescent↗

PubMed1991

Pelvic floor muscles response to graded rectal distension and cutaneous stimulation.

The responses of the external ani sphincter (EAS) and the levator ani (LA) muscles to graded rectal distension and to cutaneous and genital stimulation were examined in 25 cats of either sex. The animals were anesthetized with sodium pentobarbital (30 mg/kg, intraperitoneal) and then tested in two positions: with hindlimbs extended and with hindlimbs flexed simulating the straining position. Graded rectal distension was performed at two speeds: 1 and 10 sec. Basal levels of activity in the EAS were higher in the straining than in the extended position (P less than 0.005). The EAS responded to rapid rectal distension with inhibition of its activity. When changed to the straining position significant increases in muscular activity were observed after 35 cc of balloon insufflation (P less than 0.005). In the same muscle, slow distension produced an initial decrease in activity followed by significant increases after insufflation of 40 cc in the extended position and of 30 cc in the straining position. Basal activity in the LA was similar in both positions tested. The main effects of rectal distension in this muscle were increases in activity, significant only after high volumes of air inflation in the straining position (P less than 0.0001). Cutaneous stimulation disclosed a receptive field that was widespread for the EAS, extending over lumbosacral dermatomes (L3-S2), but greatly restricted for the LA. Responses to vaginal and cervical stimulation were more reliably obtained from the LA (P less than 0.001). These differences indicate that the EAS and LA muscles of the cat correspond with distinct, although related neural circuits.

Animals↗

PubMed1991

Adrenal steroids and the physiopathology of a subset of depressive disorders.

Patients suffering from Cushing's disorders (syndrome and disease) are significantly affected by psychological disturbances that overlap with depressive disorders. In turn, a subset of patients with affective disorders present with hypercortisolemia, and non-suppression in the Dexamethasone Suppression Test (DST). We have shown that long-term potentiation (LTP), a putative memory mechanism, is significantly affected by steroids when tested on the hippocampus, a crucial structure for memory processes. We propose that an imbalance of adrenal steroids and their metabolites, interacting at the level of the hippocampus, play a fundamental role in the psychophysiopathology of Cushing's and depressive disorders. By biasing memory mechanisms, the imbalance of these hormones sets both distorted mood, and hence memory contents, and distorted cognition based on recollection and present experiences.

Adrenal Cortex Hormones↗