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.

Steroids, neuroactive steroids and neurosteroids in psychopathology.

The term "neurosteroid" (NS) was introduced by Baulieu in 1981 to name a steroid hormone, dehydroepiandrosterone sulfate (DHEAS), that was found at high levels in the brain long after gonadectomy and adrenalectomy, and shown later to be synthetized by the brain. Later, androstenedione, pregnenolone and their sulfates and lipid derivatives as well as tetrahydrometabolites of progesterone (P) and deoxycorticosterone (DOC) were identified as neurosteroids. The term "neuroactive steroid" (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. NASs bind and modulate different types of membrane receptors. The GABA and sigma receptor complexes have been the most extensively studied, while glycine-activated chloride channels, nicotinic acetylcholine receptors, voltage-activated calcium channels, although less explored, are also modulated by NASs. Within the glutamate receptor family, N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors have also been demonstrated to be a target for steroid modulation. Besides their membrane effects, once inside the neuron oxidation of Ring A reduced pregnanes, THP and THDOC, bind to the progesterone intracellular receptor and regulate gene expression through this path. The involvement of NASs on depression syndromes, anxiety disorders, stress responses to different stress stimuli, memory processes and related phenomena such as long-term potentiation are reviewed and critically evaluated. The importance of context for the interpretation of behavioral effects of hormones as well as for hormonal levels in body fluids is emphasized. Some suggestions for further research are given.

[Neurobiology of depression and stress syndromes. Focus on active neurosteroids and neurosteroids]. / Neurobiología de los síndromes depresivos y de estrés. Enfocado sobre los neuroesteroides y los neuroesteroides activos.

That the brain is a target for hormones is a well established fact. Today we also know that brains can secrete the whole gamut of peptides and steroid hormones, i.e., pregnanes and pregnenes. Considering that the ancestral neuron was a neurosecreting cell, this is not surprising. As CRH and cortisol secretion occur in situ in nervous systems, the intriguing possibility that anxio-depressive syndromes may be associated with paracrine effects of these compounds on the brain should now be considered. The concept of stress as a specific reaction of the nueroendocrine system to nocuous stimuli is re-examined in light of new evidence. The fundamental importance of historical, social, and psychological contexts in evaluating hormonal actions is emphasized. Problems emerging from the attempt to search for specific biological markers in different psychiatric disorders are discussed. The suggestion is made that, rather than to categorize nosological entities, biological dysfunctions should be elated with psychological abnormalities.

Effects of the active neurosteroid allotetrahydrodeoxycorticosterone on long-term potentiation in the rat hippocampus: implications for depression.

We studied the effects of the active neurosteroid (ANS) allotetrahydrodeoxy corticosterone (ATHDOC) on long-term potentiation (LTP) in the dentate gyrus (DG) of intact, urethane anesthetized rats. Intravenous injection of the hormone at two doses, 0.1 and 0.5 mg/kg, produced a significant decrease in both components of the response: excitatory postsynaptic potentials (EPSP) and population spikes (PS). The effects were similar for the two doses. The results are discussed in terms of the potential mechanism by which ATHDOC modulates neural processes associated with symptoms present in depression syndromes.

Neurobiología de los síndromes depresivos y de estrés. Enfocado sobre los neuroesteroides y los neuroesteroides activos / [Neurobiology of depression and stress syndromes. Focus on active neurosteroids and neurosteroids]

That the brain is a target for hormones is a well established fact. Today we also know that brains can secrete the whole gamut of peptides and steroid hormones, i.e., pregnanes and pregnenes. Considering that the ancestral neuron was a neurosecreting cell, this is not surprising. As CRH and cortisol secretion occur in situ in nervous systems, the intriguing possibility that anxio-depressive syndromes may be associated with paracrine effects of these compounds on the brain should now be considered. The concept of stress as a specific reaction of the nueroendocrine system to nocuous stimuli is re-examined in light of new evidence. The fundamental importance of historical, social, and psychological contexts in evaluating hormonal actions is emphasized. Problems emerging from the attempt to search for specific biological markers in different psychiatric disorders are discussed. The suggestion is made that, rather than to categorize nosological entities, biological dysfunctions should be elated with psychological abnormalities.

Neurobiología de los síndromes depresivos y de estrés. Enfocado sobre los neuroesteroides y los neuroesteroides activos. / [Neurobiology of depression and stress syndromes. Focus on active neurosteroids and neurosteroids]

That the brain is a target for hormones is a well established fact. Today we also know that brains can secrete the whole gamut of peptides and steroid hormones, i.e., pregnanes and pregnenes. Considering that the ancestral neuron was a neurosecreting cell, this is not surprising. As CRH and cortisol secretion occur in situ in nervous systems, the intriguing possibility that anxio-depressive syndromes may be associated with paracrine effects of these compounds on the brain should now be considered. The concept of stress as a specific reaction of the nueroendocrine system to nocuous stimuli is re-examined in light of new evidence. The fundamental importance of historical, social, and psychological contexts in evaluating hormonal actions is emphasized. Problems emerging from the attempt to search for specific biological markers in different psychiatric disorders are discussed. The suggestion is made that, rather than to categorize nosological entities, biological dysfunctions should be elated with psychological abnormalities.

Evolutionary psychiatry. Adaptationist and nonadaptationist conceptualizations.

Darwin's theory of evolution, and in particular one of its mechanisms, natural selection, is being used as the explanatory cornerstone of many unsolved problems in human biology and human affairs. Psychiatry is an example of that. Darwinian psychiatry's main proponents endorse the adaptationist program to carry out their project to implement an evolutionary psychiatry. The adaptationist program is an attempt to view all evolutionary novelties as adaptations, i.e., classically, features that favour survival and/or reproduction. This position is definitely teleological, and anthropomorphism plays a central role in its construction. This paper takes issue with the adaptationist approach. We argue that organism-environment interactions are bidirectional processes. Hence, as a result of the fact that "a surprisingly large amount of the environment, which affects natural selection on an animal is the more or less direct result of the animals own behavior" [Waddington, C.H., 1976. Evolution of the subhuman world. In: Jantsch, E., Waddington, C.H. (Eds.), Evolution of Consciousness. London, UK, pp. 11-23], a more appropriate term to describe these interactions appears to be construction rather than adaptation alone [Lewontin, R., 2000. The triple helix: gene organism and environment. Harvard Univ. Press]. We present factual anatomical, physiological and clinical data critical of the platonic Kraepelinean classification of mental diseases, and claim that this classification is contrary to modern ideas on the evolution of nervous systems. We argue against the view of mainstream evolutionary psychiatrists that mental diseases are adaptations. We do so on two accounts. One is methodological; authors in this position do not ask whether every disease has evolutionary causes, but assume this in order to explain all diseases in such terms. The other mistake is biological; it is their belief that adaptation is the driving force of evolution while in fact it is just an outcome of evolution. The current status of the controversy between cognitive versus emotional experiences as essentially independent is reviewed, and evidence is presented, that they cannot be considered platonic, categorically independent functions of CNSs. These data, taken together, plus arguments derived from the high degree of plasticity of nervous systems, lead us to suggest a different approach to classification of mental diseases.