Progress in brain research
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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 Here we present published and unpublished pharmacological data on the most widely used agonists, antagonists and labelled ligands.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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There has been significant recent growth in programmes evaluating preventive treatment for individuals exhibiting prodromal symptoms, at high risk of developing first-episode psychosis. Because of the tremendous human and economic burden of schizophrenia and other psychotic disorders, primary prevention modalities of even modest impact would likely have important public health consequence. Several published clinical trials suggest that antipsychotic medications have beneficial effects in either preventing or postponing the emergence of first-episode psychosis in individuals at high risk of psychosis. ⋯ In one such study, low-dose risperidone pre-treatment prevented behavioural abnormalities following neonatal hippocampal lesions, while higher risperidone pre-treatment was ineffective. These findings support the predictive validity of the neonatal hippocampal lesion model in identifying psychosis prevention interventions, provide theoretical support for the use of low-dose risperidone in prevention of first-episode psychosis and suggest the possibility that higher risperidone doses could be less effective than low dosages in this application. These observations also suggest a potential role for selective 5-HT(2A) receptor antagonists as drug development targets for psychosis prevention.
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Serotonin and dopamine are two monoamines which are known to interact with each other. Their role for suicidal behaviour, aggression and mood are reviewed in this chapter. We found a substantial amount of evidence for the relevance of a serotonin and dopamine model of aggression, and for aggression as a major risk factor for suicide. Evidence was found that serotonin and dopamine also may be involved in depressed mood, and possibly the individual's ability to cope with imminent suicidality.
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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.
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This chapter describes current findings from the research into postoperative cognitive dysfunction (POCD) following cardiac and non-cardiac surgery in older adults. The evidence suggests that a significant proportion of patients show POCD in the early weeks following surgery and anesthesia. Specific domains of cognition are affected, especially memory. ⋯ Increasing age is among the most consistently reported patient-related risk factor. Other factors more directly related to the surgery and anesthesia are likely to contribute to the pathogenesis of POCD, including inflammatory processes triggered by the surgical procedure. Animal studies have provided valuable findings otherwise not possible in human studies; these include a correlation between the inflammatory response in the hippocampus and the development of POCD in rodents.