Progress in brain research
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In the kidney, the actions of the antidiuretic hormone arginine vasopressin (AVP) renders the collecting duct highly permeable to water. This large increase in water permeability is largely due to the translocation of the water channel aquaporin-2 (AQP-2) from intracellular storage vesicles to the apical plasma membrane of collecting duct principal cells. The focus of this chapter is on the recent advances in interpreting the complex mechanism that causes regulated exocytosis of AQP-2 to the apical plasma membrane, its regulated endocytosis and the recycling of AQP-2. Determining how AQP-2 trafficking occurs at the molecular level is fundamental to understanding the physiology of water balance regulation and the pathophysiology of water balance disorders.
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Synaptic plasticity has often been argued to play an important role in learning and memory. The discovery of long-term potentiation (LTP) and long-term depression (LTD), the two most widely cited cellular models of synaptic plasticity, significantly spurred research in this field. ⋯ In this review, we discuss a number of recent advancements in the understanding of the mechanisms that mediate LTP and LTD in the rodent hippocampus and focus on the use of subunit-specific N-methyl-d-aspartate receptor antagonists and interference peptides as potential tools to study the role of synaptic plasticity in learning and memory. By using the modulation of synaptic plasticity and hippocampal-dependent learning and memory by acute stress as an example, we review a large body of convincing evidence indicating that alterations in synaptic plasticity underlie the changes in learning and memory produced by acute stress.
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Here we review the functional anatomy of brainstem circuits important for triggering saccades. Whereas the rostral part of the superior colliculus (SC) is considered to be involved in visual fixation, the caudal part of the SC plays an important role in generation of saccades. We determined the neural connections from the rostral and caudal parts of the SC to inhibitory burst neurons (IBNs) and omnipause neurons (OPNs) in the nucleus raphe interpositus. ⋯ Further, IBNs receive disynaptic inhibition from the rostral part of the SC, on either side, via OPNs. Intracellular recording revealed that OPNs receive excitation from the rostral parts of the bilateral SCs, and disynaptic inhibition from the caudal SC mainly via IBNs. The neural connections determined in this study are consistent with the notion that the "fixation zone" is localized in the rostral SC, and suggest that IBNs, which receive monosynaptic excitation from the caudal "saccade zone," may inhibit tonic activity of OPNs and thereby trigger saccades.
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Oxytocin (OT) and vasopressin (AVP) mediate their biological actions by acting on four known receptors: The OT (uterine) and the AVP V(1a) (vasopressor), V(1b) (pituitary), V(2) (renal) receptors and a fifth putative AVP V(1c)? (vasodilating) receptor. This presentation will summarize some highlights of the recent progress, in the design and synthesis of selective peptide agonists, antagonists, radioiodinated ligands, fluorescent ligands and bivalent ligands for these receptors. Here we present published and unpublished pharmacological data on the most widely used agonists, antagonists and labelled ligands. ⋯ Despite much early promise, no non-peptide V(1a) or OT antagonists are currently in clinical trials. While a number of orally active non-peptide V(2) antagonists (Vaptans); notably, Tolvaptan, Lixivaptan and Satavaptan, are currently in Phase III clinical trials; to date, only the mixed V(2)/V(1a), antagonist Conivaptan (Vaprisol), has been approved by the US FDA for clinical use (by i.v. administration), for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Promising new non-peptide V(1b) and OT antagonists, as well as non-peptide V(2) and OT agonists are now in pre-clinical development.
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Converging evidence from both human and animal studies has highlighted the pervasive role of two neuropeptides, oxytocin (OXT) and arginine vasopressin (AVP), in mammalian social behaviours. Recent molecular genetic studies of the human arginine vasopressin 1a (AVPR1a) and oxytocin (OXTR) receptors have strengthened the evidence regarding the role of these two neuropeptides in a range of normal and pathological behaviours. Significant association between both AVPR1a repeat regions and OXTR single nucleotide polymorphisms (SNPs) with risk for autism has been provisionally shown which was mediated by socialization skills in our study. ⋯ Future studies should profitably focus on pharmacogenomic and genomic imaging strategies facilitated by the ease and efficacy of manipulating AVP-OXT neurotransmission by intranasal administration. Importantly, physiological measures, behavioural paradigms and brain activation can be informed by considering between-group and also within-group individual differences defined by common polymorphisms. Ultimately, investigators should strive to develop a cohesive model explaining how genomic variations are translated into individual and group differences in higher-order social behaviours.