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    By Z. Tamkosch. Mayville State University. 2018.

    Alter- ization and immunocytochemical maps buy discount anacin 525mg online, studies of previ- native splicing is common and occurs for a number of 5- ously recognized 5-HT receptors could be directed more HT receptors 525 mg anacin visa, including the 5-HT2C 525 mg anacin with visa, 5-HT4, and 5-HT7 precisely toward neurons and model cell lines that express receptors. The two splice variants of the 5-HT2C receptor these specific 5-HT receptor subtypes. Moreover, by the described in the literature encode severely truncated pro- use of cloning techniques, investigations could be initiated teins with no obvious function (6–8). In contrast, the splice to determine the functional role of previously unrecognized variants of the 5-HT4 receptor (5-HT4(a)–5-HT4(f)) and 5-HT receptors (e. Concur- 5-HT7 receptor (5-HT7(a)–5-HT7(d)) differ in length and rently, much progress has been made in delineating the composition in the carboxyl terminus (see refs. Marked species differences and perhaps regional subtypes. The focus of this review is on the molecular and differences lead to different patterns of splicing. Aghajanian: Departments of Psychiatry and Pharmacology, molecule. Splice variants of the 5-HT receptor have no 7 Yale University School of Medicine, New Haven, Connecticut. Elaine Sanders-Bush: Department of Pharmacology, Vanderbilt Univer- known functional differences. In contrast, a second form sity School of Medicine, Nashville, Tennessee. It is not known whether other ing properties of this ligand-gated ion channel (see ref. It seems likely that the RNA editing in mammalian systems was discovered 5-HT2C receptor would not be unique. However, screening about a decade ago and is defined as any modification, other methods for reliably detecting RNA editing are not avail- than alternative splicing, that occurs at the level of mRNA. Conse- editing generally involves the conversion of adenosine resi- quently, new edited substrates are slow to emerge. Such editing events have the potential to alter the genetic code at the level of RNA; the resulting is the Post-translational Regulation formation of multiple protein isoforms with altered func- tion. The discovery of RNA editing of the 5-HT receptor Receptor desensitization and down-regulation are common 2C provided the first, and so far only, example of editing of a adaptive responses to sustained agonist exposure. Editing of the human 5- widely accepted model of desensitization of G protein-cou- HT receptor mRNA involves five sites, A through E, pled receptors is based on extensive studies of the -adrener- 2C where adenosine is converted to inosine; inosine substitutes gic receptor, a G -linked receptor. In a simplified renditions for guanosine in the genetic code, thus generating different of the model, agonist binding to a cell surface receptor leads protein isoforms. Multiple RNA isoforms have been found to receptor phosphorylation, arrestin binding, receptor in- for the 5-HT receptor in human brain, predicting the ternalization into endosomes, dephosphorylation of the re- 2C formation of protein isoforms with up to three amino acids ceptor, and recycling back to the cell surface. Receptor phos- changed in the second intracellular loop of the receptor (15, phorylation is thought to mediate desensitization by 16). Editing at the A, B, C, and D adenosine residues of uncoupling the receptor from G protein. For many recep- human 5-HT -receptor mRNA leads to predicted changes tors, this phosphorylation event is promoted by a family 2C in all three amino acids to yield valine, serine, valine (VSV) of G protein-coupled receptor kinases (GRKs). However, at positions 156, 158, and 160 rather than isoleucine, aspar- second messenger-dependent kinases and protein kinases C agine, isoleucine (INI) at these positions in the unedited and A, in addition to GRKs, have all been implicated in receptor isoform (Fig. Editing at all five sites predicts the desensitization of 5-HT1A receptor (18). Abundant in the formation of the valine, glycine, valine (VGV) isoform. These studies have shown that ed- raphe 5-HT1A autoreceptors has been proposed to play a ited receptor isoforms couple less efficiently to Gq proteins, role in the delayed therapeutic onset of antidepressant drugs evidenced by lowered agonist potencies to activate phospho- (see ref.

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    That inhibitory adrenergic input tion by serotonin fibers also exists; the origin of this projec- also arises from the PGi is revealed when the strong gluta- tion has not been determined discount anacin 525 mg without prescription. Ultrastructural analyses have mate input is antagonized pharmacologically (30) 525 mg anacin with visa. Inputs shown that several of these inputs directly innervate LC to distal LCdendrites from the amygdala (9) or NTS (10) neurons (16–20) cheap anacin 525 mg mastercard. Our unpublished studies in monkey indicate that the tion presumably originates in the hypothalamus (the sole anterior cingulate cortex strongly innervates the LC(32). Finally, mammillary histamine cells, and cholinergic neurons of the our recent studies using transsynaptic retrograde tracing re- brainstem). Initial studies of this peptide suggested a role in veal that the suprachiasmatic nucleus is a prominent indirect feeding (24,25). However, more recent work has stimulated afferent to the LC(34–36). This is the first demonstration considerable interest in this neurotransmitter by closely of a circuit that links the circadian suprachiasmatic nucleus linking its function to sleep regulation. Specifically, muta- mechanism with the arousal/alerting LCsystem. Inasmuch tions of the gene that makes a hypocretin receptor (26), or as other studies have linked circadian disturbances with Chapter 4: Norepinephrine 49 depression (37), and the LCsystem is also associated with that alter cAMP (51). This is significant because electrotonic depression and other mood disorders (38), this pathway coupling allows rapid, powerful cell-to-cell communication may also be important for affective function. Once rele- gated to the domain of the esoteric but unimportant, elec- Topography of LC Efferents trotonic coupling is now being demonstrated in an increas- It is well-known that LCaxons are highly branched and ing number of central neurons. Of great interest is the fact have extensive efferents that ramify throughout the central that such coupling is readily modulated by other inputs to nervous system, providing NE innervation at all levels of coupled cells—for example, in the retina, coupling is the neuraxis (see ref. Previous studies have strongly attenuated by dopamine inputs in a cAMP/protein found topography among these efferent projections (39), kinase A manner. This line of work is very promising in but the degree of specificity for projections of different LC neuropsychopharmacology because it suggests a novel set neurons appears to be quite limited. Recent studies by of targets (receptors that regulate electrotonic coupling) that Simpson et al. They report that LCneurons selectively collateralize tion of systems important in mental function and dysfunc- to different nuclei of the somatosensory system, so that indi- tion (such as the LC). Our recent work (described below) vidual neurons are more likely to send branches to thalamic shows how modulation of such coupling can have profound and cortical areas within the somatosensory system than to, influences on behavior and cognitive performance (33). LC Activity, Electrotonic Coupling, and Cognitive Performance in Behaving A2 NE Neurons of the CaudalMedulla Monkeys Norepinephrine neurons in the A2 group (caudal NTS) A possible role for electrotonic coupling among LCneurons have recently been implicated in behavioral functions of in cognitive performance was revealed by combining our psychiatric importance. Previously relegated solely to auto- recordings of LCneurons in monkeys performing a signal nomic and visceral control (e. In these ascending projections of these NE cells to forebrain areas recordings, LCneurons exhibited two modes of activity dur- such as the hypothalamus (42), bed nucleus of the stria ing task performance: a phasic mode, in which LCcells terminalis (BNST) (43), nucleus accumbens (44), and responded phasically to target stimuli, and a tonic mode, amygdala (45,46) have now been shown also to be impor- in which the tonic baseline activity of LCneurons was high tant in affective and cognitive processes (43,47). Moreover, the pha- scribed below, these findings identify new circuits for under- sic mode corresponded closely to focused attention and standing affective and mnemonic functions. Task perfor- NEUROPHYSIOLOGY mance could be improved by systemic or local (intra-LC) injection of clonidine during poor performance, which indi- Several recent findings regarding the neurophysiology of LC cates a causal influence of these patterns of LCactivity on neurons have extended our understanding of this system. A neural network model was constructed to Notably, integration of studies at the cellular and behavioral investigate mechanisms involved in generating these modes levels indicates a potentially important role of coupling of LCactivity and the corresponding task performance. Space limitations prohibit a full discussion of the findings, which are reported and reviewed in recent publications (33, 54). In brief, the model showed that modulated electrotonic Electrotonic Coupling coupling among LCneurons could produce the patterns Experiments by Christie and Williams and colleagues of LCfiring observed in the monkeys, and that known (48–50) showed that LCneurons may be regulated by elec- modulatory effects of NE could then translate these modes trotonic coupling, not only during development but also in of LCactivity into corresponding levels of task performance, adults. Additional studies by these workers indicate that also observed in the monkeys (Figs. These such coupling may be modulated by inputs to LCneurons findings have a number of implications for neuropsycho- 50 Neuropsychopharmacology: The Fifth Generation of Progress A,B C,D FIGURE 4. Simulation of locus ceruleus (LC) activity by modulated electrotonic coupling.

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    Innovation in the alliances in case A1 built on established relations between acute providers purchase anacin 525 mg mastercard. Even in the less developed cases generic anacin 525mg without prescription, such as case E1 discount anacin 525mg on line, achievements have built on existing relationships. Finally, Table 8 suggests a number of reasons why achieving coherence in clinical leadership across the three arenas may be difficult. Elaborate and far-reaching service redesigns over a wide geography can preoccupy clinical leaders when creating plans in strategic and operational commissioning arenas (points 1 and 2 in Figure 24). This sometimes detracts from the development of operational detail. It may also deflect effort away from building normative networks among front-line provider staff (cases E1 and F). Additionally, committed normative networks may emerge within providers, particularly among GPs who have been inspired by the aspirations of CCGs, but perhaps found that the realities of opportunities for influence have not lived up to their expectations. Such situations can lead to confusion and something of a vacuum at the operational commissioning level (point 2, see Figure 24), as delivery leaders recruit different NHS strategic initiatives to serve their purposes (case D). Notably, in case D, innovations in primary care were driven not by GPs as commissioners using the CCG as the lever, but rather by GPs as providers using GP federations as the vehicle for change. There were service innovations built around telephone triage, new workforce designs, self-care, targeted work with the frail elderly using specialist teams of GPs with special interest, pharmacists and specialist nurses. Some of the major clinical innovators involved in these initiatives were of the view that the CCGs were simply not delivering and the service and the patient simply could not wait for them. Thus, they said, the provider side needed to get on with the redesign and present it to the commissioners as a new offer. Although these initiatives were undoubtedly examples of clinically led service redesign, they were often stymied by the lack of a receptive and sufficiently resourced operational commissioning forum to consider them. Conclusions This chapter has analysed the role of clinical leadership in our eight cases in terms of three arenas, concerned with strategic commissioning, operational commissioning and operational service delivery. We have also made a distinction between the leadership work of instigating service redesign and that of implementing new models or concepts of service delivery. In addition, we examined the range of ways that these activities can take place across the three arenas. A number of key points are worth bringing out by way of conclusion to our comparison of the eight cases. First, the leadership work of crafting operational detail is bound up with the operational delivery arena – without leadership work within this arena, operational solidity is unlikely to emerge. However, this institutional work of defining operational detail requires interchange with the operational commissioning arena, so that the staff and other resources or delivery are appropriate and also so that there can be iterative refinement of the overall concept and its ethos. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 81 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. CROSS-CASE FINDINGS AND COMPARISONS Second, and perhaps more surprising, the leadership work of envisaging and articulating new service concepts can begin in any of the three arenas and often involves individuals who can move adroitly between them. We saw new service concepts being taken up to the strategic arena by clinicians who were also engaged in committed work in operational arenas, as well as cases where clinicians working mainly in strategic arenas formulated big ideas and found formal and informal ways of shaping powerfully the activities of colleagues in the other two kinds of arena. Above all, our analysis brings out the key role played by operational commissioning arenas for steering service innovation. Arenas such as programme boards appear to offer a forum where clinical leaders in CCG commissioning roles and in provider roles come together to integrate the institutional work of creating new models of service delivery. In order to do this, they can be seen as bringing clinical expertise and experience to bear in reconciling a number of perspectives which are potentially in conflict with one another.

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    Serotonergic and nora- pared to -nonpreferring (NP) rats buy anacin 525 mg fast delivery. Pharmacol Biochem Behav drenergic dysregulation in alcoholism: m-chlorophenylpipera- 1993;46:173–177 purchase anacin 525 mg without prescription. Am J Psychiatry 1996;153:83– sumption in null mutant mice lacking 5-HT1B serotonin recep- 92 buy anacin 525mg cheap. Serotonin2C receptors and sero- functional polymorphisms of the alcohol-metabolism genes in Chapter 98: Vulnerability Factors for Alcoholism 1411 protection against alcoholism. Meta-analysis of the effects of alcohol dehydro- 795–807. Prevalence, onset, Jewish men in Israel: a pilot study. J Stud Alcohol 1998;59: and risk of psychiatric disorders in men with chronic low back 133–139. Nu- tion is accepted as a pleasurable pastime and even an en- merous studies have shown that alcoholism is familial. In hancer of health and well-being, it has historically been ob- the National Comorbidity Survey of 5,877 individuals, it served that a sizable minority is unable to keep within safe was found that alcohol use disorders aggregate significantly limits of consumption. Such individuals may abuse alcohol in families with an odds ratio of 1. Alcoholism is today among the most holic parent is a significant risk factor for the development pervasive psychiatric disorders. In the United States, the of the disease; children of alcoholics are five times more lifetime prevalence of alcohol dependence, the severe form likely to develop alcohol-related problems than children of of alcoholism, is 8% to 14% (1). It has been shown that the transmission dence to abuse is 1. Individuals often maintain a pattern of the vulnerability to alcoholism from parents to their of alcohol abuse without dependence for many years (2). Serious drinking frequently begins in adolescence, and ap- Studies of heritability, a measure of the genetic compo- proximately 40% of alcoholics develop their first symptoms nent of variance in interindividual vulnerability, indicate of addiction between the ages of 15 and 19 years (3). As that genetic influences are substantially responsible for the discussed in this chapter, heritability studies suggest that an observed patterns of familiality. Comparative studies across populations suggest holism in children even when the child is reared by unre- that sociocultural factors determine differences in thresholds lated adoptive parents (7,8). Large, well-constructed twin above which an individual is likely to go beyond social studies (8–10) have demonstrated that genetic factors are drinking and slip into abuse or addiction. Is the develop- important in determining vulnerability to alcoholism, par- ment of alcoholism due to a unique set of biochemical and ticularly in the more severe forms of the disease (11). Are there preexisting behav- been performed using the population-based Virginia Twin ioral traits that predispose to alcoholism? Caucasian female twin pairs of the questions addressed by this chapter. Some of the environmental influences are uniquely nonshared environmental factors, which is most accurately experienced by the individual (nonshared) and some are labeled as 'other,' including as it does other sources of variance such as measurement error (12). The results of these two studies were confirmed in a recent analysis of 5,091 U. This study also added the information Health, Bethesda, Maryland. Compared recent evaluation of the co-inheritance of alcoholism and with the expected genetic correlations of 0. Female twins from the Virginia Twin dence interval (CI) 4% to 45%] for opposite-sex pairs.

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