In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Stress and the brain: from adaptation to disease

A review of central 5-HT receptors and their function

It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).

In this review, we have described the function of MR and GR in hippocampal neurons. The balance in actions mediated by the two corticosteroid receptor types in these neurons appears critical for neuronal excitability, stress responsiveness, and behavioral adaptation. Dysregulation of this MR/GR balance brings neurons in a vulnerable state with consequences for regulation of the stress response and enhanced vulnerability to disease in genetically predisposed individuals. The following specific inferences can be made on the basis of the currently available facts. 1. Corticosterone binds with high affinity to MRs predominantly localized in limbic brain (hippocampus) and with a 10-fold lower affinity to GRs that are widely distributed in brain. MRs are close to saturated with low basal concentrations of corticosterone, while high corticosterone concentrations during stress occupy both MRs and GRs. 2. The neuronal effects of corticosterone, mediated by MRs and GRs, are long-lasting, site-specific, and conditional. The action depends on cellular context, which is in part determined by other signals that can activate their own transcription factors interacting with MR and GR. These interactions provide an impressive diversity and complexity to corticosteroid modulation of gene expression. 3. Conditions of predominant MR activation, i.e., at the circadian trough at rest, are associated with the maintenance of excitability so that steady excitatory inputs to the hippocampal CA1 area result in considerable excitatory hippocampal output. By contrast, additional GR activation, e.g., after acute stress, generally depresses the CA1 hippocampal output. A similar effect is seen after adrenalectomy, indicating a U-shaped dose-response dependency of these cellular responses after the exposure to corticosterone. 4. Corticosterone through GR blocks the stress-induced HPA activation in hypothalamic CRH neurons and modulates the activity of the excitatory and inhibitory neural inputs to these neurons. Limbic (e.g., hippocampal) MRs mediate the effect of corticosterone on the maintenance of basal HPA activity and are of relevance for the sensitivity or threshold of the central stress response system. How this control occurs is not known, but it probably involves a steady excitatory hippocampal output, which regulates a GABA-ergic inhibitory tone on PVN neurons. Colocalized hippocampal GRs mediate a counteracting (i.e., disinhibitory) influence. Through GRs in ascending aminergic pathways, corticosterone potentiates the effect of stressors and arousal on HPA activation. The functional interaction between these corticosteroid-responsive inputs at the level of the PVN is probably the key to understanding HPA dysregulation associated with stress-related brain disorders. 5. Fine-tuning of HPA regulation occurs through MR- and GR-mediated effects on the processing of information in higher brain structures. Under healthy conditions, hippocampal MRs are involved in processes underlying integration of sensory information, interpretation of environmental information, and execution of appropriate behavioral reactions. Activation of hippocampal GRs facilitates storage of information and promotes elimination of inadequate behavioral responses. These behavioral effects mediated by MR and GR are linked, but how they influence endocrine regulation is not well understood. 6. Dexamethasone preferentially targets the pituitary in the blockade of stress-induced HPA activation. The brain penetration of this synthetic glucocorticoid is hampered by the mdr1a P-glycoprotein in the blood-brain barrier. Administration of moderate amounts of dexamethasone partially depletes the brain of corticosterone, and this has destabilizing consequences for excitability and information processing. 7. The set points of HPA regulation and MR/GR balance are genetically programmed, but can be reset by early life experiences involving mother-infant interaction. 8. (ABSTRACT TRUNCATED)

/pdf/brain-corticosteroid-receptor-balance-in-health-and-disease-1s4dl9ggav.pdf

Brain corticosteroid receptor balance in health and disease.

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior.

In this study, we examined the interaction of 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex (mPFc) using the techniques of extracellular single unit recording and microiontophoresis. The iontophoresis of the selective 5-HT1A receptor agonist (+-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced a current-dependent suppression (2.5-20 nA) of the basal firing rate of spontaneously active mPFc cells. The iontophoretic (5-10 nA) and systemic administration (0.1-0.5 mg/kg, i.v.) of the 5-HT2A/5-HT2C receptor antagonist ritanserin and the selective 5-HT2A receptor antagonist MDL 28727 significantly potentiated and prolonged 8-OHDPAT's suppressant action. In addition, the systemic administration of another selective 5-HT2A antagonist MDL 100907, but not its less active enantiomer MDL 100009, also potentiated and prolonged 8-OHDPAT's action. The potentiating effect of the 5-HT2A receptor antagonists on the action of 8-OHDPAT is specific in that neither the iontophoresis of ritanserin nor MDL 28727 altered the suppressant action produced by the iontophoresis of the 5-HT3 receptor agonist 2-methylserotonin onto mPFc cells. Moreover, the suppressant action of 8-OHDPAT was not altered by the systemic administration of the selective 5-HT3 receptor antagonist granisetron (0.1-0.5 mg/kg, i.v.). On the other hand, the iontophoresis of a low current (0.5 nA) of the 5-HT2A,2C receptor agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potentiated the excitation induced by the iontophoresis of l-glutamate on quiescent mPFc cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: an iontophoretic study.

5-HT1B mRNA regulation in two animal models of altered stress reactivity

Effects of bilateral adrenalectomy on the induction of learned helplessness behavior.

Effects of 5-HT1A receptor agonists on hypothalamo-pituttary-adrenal axis activity and cortlcotropin-releasing factor containing neurons in the rat brain

Emmeline Edwards

Papers

Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior.

Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: an iontophoretic study.

5-HT1B mRNA regulation in two animal models of altered stress reactivity

Effects of bilateral adrenalectomy on the induction of learned helplessness behavior.

Effects of 5-HT1A receptor agonists on hypothalamo-pituttary-adrenal axis activity and cortlcotropin-releasing factor containing neurons in the rat brain