Corticosteroid receptor hypothesis

AB - Corticosteroids are released by the adrenal cortex with a diurnal rhythm and in response to stressful environmental changes. They not only act on peripheral organs, but also regulate brain physiology, thereby affecting mental processes like emotion and cognition. Here, we discuss the role of the two known corticosteroid receptors-glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)-in the brain by summarizing the results obtained with various genetically modified mouse lines. In these lines, either the GR or the MR gene has been targeted or GR protein levels have been upregulated or downregulated. Analysis of the different lines confirms the importance of GR in the regulation of the hypothalamic pituitary adrenal (HPA) axis because interference with GR activity activates the HPA axis, whereas increased GR protein levels inhibit HPA axis activity. Genetic downregulation of GR protein levels and inactivation of the GR gene in the brain reduce anxiety-related behavior, which reveals a central role of GR in emotional behavior. Both HPA axis activity and anxiety are modulated by corticotropin releasing hormone (CRH); therefore, we include in the discussion results obtained with genetically modified CRH or CRH receptor mice. We further address the important role of corticosteroid receptors for hippocampal function and integrity. Cellular properties of CA1 neurons are changed, and hippocampal-dependent explicit memory is affected in GR mutant animals. Comparing MR and GR mutant animals suggests the requirement of MR but not GR for dentate gyrus granule cell maintenance. Because an imbalance in glucocorticoid levels is associated with cognitive impairments and mental disorders, the described mouse lines will aid in understanding the mechanisms involved in the pathology of these disorders.

An example of an acute hepatitis-like syndrome arising after pulse methylprednisolone therapy.  These episodes arise typically 2 to 4 weeks after a third or fourth cycle of pulse therapy, and range in severity from an asymptomatic and transient rise in serum aminotransferase levels to an acute hepatitis and even fulminant hepatic failure.  In this instance, the marked and persistent rise in serum enzymes coupled with liver histology suggesting chronic hepatitis led to a diagnosis of new-onset autoimmune hepatitis, despite the absence of serum autoantibodies or hypergammaglobulinemia.  Autoimmune hepatitis may initially present in this fashion, without the typical pattern of serum autoantibodies during the early, anicteric phase.  The diagnosis was further supported by the prompt improvements in serum enzymes with prednisone therapy.  The acute hepatitis-like syndrome that can occur after pulses of methylprednisolone is best explained as a triggering of an underlying chronic autoimmune hepatitis caused by the sudden and profound immunosuppression followed by rapid withdrawal.  This syndrome can be severe, and fatal instances have been reported.  Whether reinitiation of corticosteroid therapy with gradual tapering and withdrawal is effective in ameliorating the course of illness is unclear, but anecdotal reports such as this one suggest that they are beneficial and should be initiated promptly on appearance of this syndrome.  Long term follow up of such cases is also necessary to document that the autoimmune hepatitis does not relapse once corticosteroids are withdrawn again.

AB - Corticosteroid receptor modulation of mesoaccumbens dopamine neurotransmission is believed to be a key neurobiological mechanism mediating the effects of stress in addiction. Importantly, nucleus accumbens (NAc) subregions (core and shell) are reported to respond differentially to fluctuating basal levels of glucocorticoids, with dopaminergic responses in the core of the NAc being somewhat impervious to fluctuating levels of glucocorticoids relative to the shell. To investigate the corticosteroid receptor mechanisms mediating basal dopamine efflux in the core of the NAc, we have used chronoamperometry in combination with stearate-modified graphite paste electrodes in urethane anesthetized male Long-Evans rats during the peak and nadir of the circadian cycle. Blockade of ventral tegmental area low-affinity glucocorticoid (GR) or high-affinity mineralocorticoid (MR) receptors with mifepristone (1 μg/μl) or spironolactone ( μg/μl), respectively, indicated that endogenous phase-dependent corticosteroid receptor activation (GRs during peak; MRs during nadir) facilitated extracellular NAc dopamine efflux. Conversely, the alternate receptor's actions appeared inhibitory at these time points (MRs during peak; GRs during nadir). Pharmacological activation of either the GR or MR with corticosterone (2 μg/μl) or aldosterone ( μg/μl), respectively, potentiated NAc dopamine efflux, irrespective of circadian phase. Together, these data suggest that dominant corticosteroid receptor activation stimulates tonic mesoaccumbens dopamine transmission, enabling MRs and GRs to differentially maintain basal NAc dopamine release over the course of the circadian cycle. This points to an important molecular mechanism through which relatively stable NAc core dopamine extracellular levels could be maintained in the face of fluctuating corticosterone circadian rhythms.

Corticosteroid receptor hypothesis

corticosteroid receptor hypothesis


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