Psychoneuroendocrinology
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Psychoneuroendocrinology · Dec 2009
ReviewThe influence of the membrane on neurosteroid actions at GABA(A) receptors.
Modern views of anesthetic neurosteroid interaction with the GABA(A) receptor conceptualize steroid ligands interacting with a protein binding site on the receptor. It has generally been assumed that the steroid interaction/binding site is contained in an extracellular domain of the receptor, and that steroid interactions are of high potency, evidenced by the low aqueous ligand concentrations required to achieve potentiation of channel function. We have been considering implications of the observations that steroids are quite lipophilic and that recently identified putative steroid binding sites are in transmembrane domains of the receptor. ⋯ These considerations have practical implications for actions of endogenous neurosteroids. Lipophilicity will tend to promote autocrine actions of neurosteroids at GABA(A) receptors within cells that synthesize neurosteroids, and lipophilic retention will limit intercellular diffusion from the source of steroid synthesis. Lipophilicity and steroid access to the receptor binding sites also must be considerations in drug design if drugs are to effectively reach the target GABA(A) receptor site.
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Psychoneuroendocrinology · Dec 2009
ReviewNeuroactive steroids: an update of their roles in central and peripheral nervous system.
After five editions, the congress on "Steroids and Nervous System" held in Torino, Italy, represents an important international event for researchers involved in this field aimed to recapitulate mechanisms, physiological and pharmacological effects of neuroactive steroids. The present review introduces manuscripts collected in this supplement issue which are based on new interesting findings such as the influence of sex steroids on cannabinoid-regulated biology, the role of steroids in pain, the importance of co-regulators in steroidal mechanisms and the understanding of new non classical mechanism, the emerging role of vitamin D as a neuroactive steroid and the pathogenetic mechanisms mediated by glucocorticoid receptors. Finally, we have integrated these aspects with an update on some of the several and important observations recently published on this hot topic.
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Psychoneuroendocrinology · Dec 2009
ReviewNeuronal plasticity: a link between stress and mood disorders.
Although stress represents the major environmental element of susceptibility for mood disorders, the relationship between stress and disease remains to be fully established. In the present article we review the evidence in support for a role of neuronal plasticity, and in particular of neurotrophic factors. Even though decreased levels of norepinephrine and serotonin may underlie depressive symptoms, compelling evidence now suggests that mood disorders are characterized by reduced neuronal plasticity, which can be brought about by exposure to stress at different stages of life. ⋯ Antidepressant treatment can normalize deficits in neurotrophin expression produced by chronic stress paradigms, but may also alter the modulation of BDNF under acute stressful conditions. In summary, there is good agreement in considering neuronal plasticity, and the expression of key proteins such as the neurotrophin BDNF, as a central player for the effects of stress on brain function and its implication for psychopathology. Accordingly, effective treatments should not limit their effects to the control of neurotransmitter and hormonal dysfunctions, but should be able to normalize defective mechanisms that sustain the impairment of neuronal plasticity.
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Psychoneuroendocrinology · Dec 2009
Neurosteroids: endogenous allosteric modulators of GABA(A) receptors.
In the mammalian central nervous system activation of the ionotropic GABA(A) receptor by the neurotransmitter GABA plays a crucial role in controlling neuronal excitability. This essential form of neuronal regulation may be subject to "fine tuning" by particular metabolites of progesterone and deoxycorticosterone, which bind directly to the GABA(A) receptor to enhance the actions of GABA. ⋯ Neurosteroid synthesis may change dynamically in a variety of physiological situations (e.g. stress, pregnancy) and perturbations in their levels are implicated in a variety of neurological and psychiatric disorders. Here we will consider (1) evidence supporting the concept that neurosteroids act as local regulators of neuronal inhibition, (2) that extrasynaptic GABA(A) receptors appear to be a particularly important neurosteroid target and (3) recent advances in defining the neurosteroid binding site(s) on the GABA(A) receptor.