B. Dubrovsky

Distribution, metabolism and biological activity of deoxycorticosterone in the central nervous system

Intravenously injected [1,2-3H]deoxycorticosterone (DOC) readily enters all parts of the central nervous system. In intact and eviscerated rats the highest concentration of radioactive label was recovered from areas corresponding to the reticular formation from the brain stem. In addrenalectomized animals, in addition to high brain stem concentration, there was also a marked increase in the uptake of radioactivity in the septum, hippocampus and pituitary. Data from the eviscerated rat point to a uniform distribution of [1,2-3H]DOC in neural tissues and suggest that the higher levels of radioactivity found in the brain stem may be due to a DOC metabolite with the chromatographic characteristics of allo-tetrahydro-DOC, an anaesthetic-type steroid. A decrease in the amplitude of evoked sciatic potentials in brain stem sites but not in the thalamic relay nucleus was observed in 52% of the cases studied, following the i.v. injection of 100-150 mug DOC.

Neurosteroids, neuroactive steroids, and symptoms of affective disorders

Neurosteroids (NS) are steroids synthesized by the brain. Neuroactive steroids (NAS) refers to steroids that, independent of their origin, are capable of modifying neural activities. NAS bind and modulate different types of membrane receptors. The gamma amino butyric acid (GABA) and sigma receptor complexes have been the most extensively studied. Oxidized ring A reduced pregnanes, tetrahydroprogesterone (THP), and tetrahydrodeoxycorticosterone (THDOC) bind to the progesterone intracellular receptor (PR), and in this way can also regulate gene expression. Animal experimentation showed that salient symptoms of depression, viz., anxiety, sleep disturbances, and memory and sexual dysfunctions, are modulated by NAS. In turn, psychotropic drugs modulate NS and NAS levels. NS levels as well as NAS plasma concentrations change in patients with depression syndromes, the levels return to normal baseline with recovery, but normalization is not necessary for successful therapy. Results from current studies on the evolution of nervous systems, including evolutionary developmental biology as well as anatomical and physiological findings, almost preclude a categorical classification of the psychiatric ailments the human brain succumbs to. The persistence in maintaining such essentialist classifications may help to explain why up to now the search for biological markers in psychiatry has been an unrewarding effort. It is proposed that it would be more fruitful to focus on relationships between NAS and symptoms of psychiatric disorders, rather than with typologically defined disorders.

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.

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.

Neurobiological aspects of the pelvic floor muscles involved in defecation

Neurobiological aspects of the organization of pelvic floor musculature are reviewed. Evolutionary considerations on the origin of these muscles indicate that they develop with specific attachments and function, i.e., do not derive from preexisting muscles such as the ones from the tail. Anatomically, pelvic floor muscles can be divided into 1) true sphincters and related muscles and 2) muscles which flank the visceral outlets. While in quadrupedal mammals the EAS behaves as a fast twitch muscle, in man this muscle has slow twitch characteristics. Like some epaxial muscles the EAS has a strong connectivity with its surrounding skin. In further analogy with some epaxial muscle the EAS, although endowed with muscle spindles, is devoid of the phasic, monosynaptic component of the stretch reflex. Onufs nucleus which innervates pelvic floor muscles receives an important group of suprasegmental afferents including, probably, direct corticospinal fibers. Pelvic floor muscles play a fundamental role in signaling arrival of feces to the perineum. While sphincteric activity is important for continence, other mechanisms such as the anorectal angle and anal cushions are also of relevance. Although emphasis has been put on motor factors, fecal incontinence can also result from impairments in sensory mechanisms of the anorectal system. In diseases like amyotrophic lateral sclerosis, Werdnig Hoffmans and others there is selective sparing of neuropathology in Onufs nucleus. In contrast, the nucleus is affected in some autonomic visceromotor neuronal disorders, e.g., Shy Drager syndrome, Fabrys disease. It has been suggested that Onufs nucleus occupies an intermediate position between visceral and somatic nuclei.

Effects of adrenal steroids and their reduced metabolites on hippocampal long-term potentiation.

We studied the effects of steroid hormones on the hippocampal long-term potentiation (LTP), a putative mechanism of neuronal plasticity and memory storage in the CNS. In vivo experiments were performed in rats under chloral hydrate anesthesia (0.4 mg/kg i.p.). All animals were adrenalectomized 48 h before recording. LTP was induced after priming tetanic stimulation at the perforant pathway (PP) and single pulse field potentials were obtained from the dentate gyrus (DG). The excitatory post-synaptic potential (EPSP) slope and population spike (PS) amplitude were analyzed before and after the i.v. injection of the steroids and after the induction of LTP, and followed up to 1 h. Results obtained with the hormones were compared with matched control animals injected with vehicle alone, Nutralipid 10%. Previous results from our laboratory showed that deoxycorticosterone (DOC) decreased the magnitude of the EPSP at all times after priming stimulation and the PS decreased during the first 30 min of the LTP. Corticosterone decreased the EPSP in the first 15 min and the PS during the first 30 min after priming stimuli. In these experiments the mineralocorticoids aldosterone and 18-OH-DOC elicited a decrease of the EPSP at all times post-train; and no significant difference against vehicle was observed in the PS. Post-injection values were not changed except for 18-OH-DOC at a dose of 1 mg, where a decrease of both the EPSP (P less than 0.01) and the PS (P less than 0.02) was observed against vehicle. ATH-progesterone at 0.1 mg/rat also decreased the EPSP values significantly after priming stimulation and no significant changes against vehicle were observed in the PS. These results show that adrenal steroids can modulate hippocampal LTP, that they can act at different neuronal loci and with different time courses in the development of the phenomena.

The role of dorsal columns in serial order acts

Abstract The ability to perform a highly integrated serial act was examined in cats with section of the dorsal columns and compared with sham-operated animals. The serial act involved accurate timing of a jump to encounter a target (piece of liver) on a rotating wheel, precise forelimb projection to release the target, visual tracking of the object in space during the jump, proper landing, and localization of the released liver on the floor within a prescribed period of time. The cats with lesions had difficulty in the proper initiation of the act and displayed a significantly lower efficiency and obvious inaccuracy in releasing the target. Further, the ability to visually follow the released object in space during the jump was impaired, a fact that hampered localization of that object on the floor after landing. This supports the belief, based on evolutionary and anatomophysiological considerations, that the dorsal columns convey elements of information necessary for the planning and execution of serial order acts.

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

SummaryHippocampal 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 formatio 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 somadendritic 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. 5α-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 EPSPs 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.

CNV and time estimation

We investigated the hypothesis that the development and resolution of CNV waves may, in part at least, reflect time estimation processes in the nervous system. Specifically, we postulated that subjects with a high degree of accuracy in time estimation tasks will show a fast resolution of the negativity following the imperative stimulus (S2). The results showed that, consistent with the hypothesis, accurate estimators, as a group, show CNVs with faster resolution of negativity after S2. In addition, they have CNVs of lower amplitude and show a slower rise time to peak negativity than subjects with poor time estimation abilities.

Effects of deoxycorticosterone and its ring A-reduced derivatives on the nervous system

We examined the effects on central nervous system excitability of deoxycorticosterone (DOC) and its ring A reduced derivatives, 5α-dihydro-DOC (DHDOC) and 3α-OH 5α-tetrahydro-DOC (THDOC). In adrenalectomized rats, under urethane anesthesia, i.p. injections of DOC, DHDOC, or THDOC 750 μg in 0.5 ml 4:1 saline, cremophor-EL solution, produced a significant decrease in the amplitude of sciatic evoked potentials in regions of the pontine brain stem. During simultaneous recording of brain stem evoked potentials and afferent volleys from L6 and L7 dorsal roots, i.v. injection of 750 μg DOC produced a decrease in the amplitude of brain stem responses without noticeable effects on the dorsal root afferent volleys. At the neuronal level, the effects of the steroid hormones were evaluated by the changes they induced in the mean firing frequency (P < 0.01) measured during 5-min intervals as determined by a one-way analysis of variance and analysis with a test of multiple comparisons. Only cells which fired in a stationary mode for 15 min before the steroid injection were studied. The effects of i.v. DOC were tested on 23 neurons. Twelve responded by a decrease in their firing rate; in the other neurons firing patterns remained unchanged. In all responsive neurons the distribution of the interval histogram showed a decrease in the peak of the shorter intervals (15 to 30 ms) and/or broader distribution extending toward longer intervals. The effects of THDOC were tested in 10 neurons. In eight of them THDOC produced a rapid (12 to 96 s, x = 35.0), significant decrease in the mean firing frequency which began to recover to control values within 6 to 20 min (x = 13.6) of steroid administration. This was associated with both a decrease in the interspike interval histogram and a shift to longer interspike intervals. The onset of the depressant effect observed with THDOC was significantly faster (P < 0.01) than that of its parent compound DOC. These results support the contention that ring A reduced metabolites of adrenal corticosteroids may fulfill an important biologic role in modulating activity of certain central nervous system regions.