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Modulation of excitatory and inhibitory transmis- ramidal cells occurs through a focal action involving a sionby multiple5-hydroxytryptamine(5-HT) receptorsin thecere- Ca2 -dependent mechanism that is not based on an in- bral cortex buy tenormin 100 mg lowest price pre hypertension pathophysiology. One of several distinguishing shown on anatomically distinct GABAergic inputs to the somato- characteristics of this alternative mechanism of transmitter basilar and apical regions tenormin 50 mg fast delivery arteria sacralis mediana, respectively buy tenormin 50 mg free shipping blood pressure chart girl, of the pyramidal cell order 100mg tenormin visa zartan blood pressure medication. This feature ap- pears to be the result of the differential involvement of two isoforms of the calcium-sensing protein synaptotagmin in 5-HT3 Receptors the two alternative release mechanisms (130). Consistent with this idea, Sr2 is highly effective in enabling 5-HT to Excitatory responses to 5-HT have been found in various induce an increase in the frequency of EPSCs in the absence central neurons that have many of the characteristics of of Ca2 (128). In cultured NG108-15 cells, the permeation proper- (131). It is possible that this late component, rather than ties of the 5-HT3 channel are indicative of a cation channel representing conventional polysynaptic transmission, is me- with relatively high permeability to Na and K and low diated through the mechanism of asynchronous transmitter permeability to Ca2 (134). A 5-HT-gated ion channel release, possibly involving a release of intraterminal Ca2 has been cloned that has physiologic and pharmacologic stores via the phospholipase C, inositol triphosphate (IP3) properties appropriate for a 5-HT3 receptor (135). An enhancement of asynchronous evoked EPSPs oocyte expression system, this receptor shows rapid desensi- via 5-HT2A receptors would provide a possible synaptic tization and is blocked by 5-HT3 antagonists (e. Its sequence homology with contrast, 5-HT itself does not promote the late component the nicotinic acetylcholine receptor (27%) and the 1 sub- of electrically evoked release except during the washout phase, unit of the GABAA receptor (22%) indicates that this 5- presumably because of opposing actions at 5-HT1 or other HT3-receptor clone is a member of the ligand-gated ion non-5-HT2A receptors (132). Typically, members of this superfam- posed location of various 5-HT-receptor subtypes and their ily are comprised of multiple subunits; however, only one interactions with other neurotransmitter receptors within 5-HT3-receptor subunit and an alternatively spliced variant cortical circuitry. Chapter 2: Serotonin 23 In hippocampus slices, 5-HT has been reported to in- the ability of these cells to respond to excitatory inputs with crease spontaneous GABAergic IPSPs, most likely through robust spike activity. A similar 5-HT3 receptor-mediated induction of The circadian rhythm in mammals is set by a pacemaker IPSCs has been reported in the neocortex (117). Whole- located primarily in the suprachiasmatic nucleus of the hy- cell patch-clamp recordings have confirmed a direct 5-HT3 pothalamus. This pacemaker activity can be maintained in receptor-mediated excitatory effect on hippocampal in- hypothalamic slices, in which suprachiasmatic neurons dis- terneurons independent of G-protein activation (139). Administration though fast, rapidly inactivating excitation has generally be- of 5-HT appears to produce a phase shift in this activity come accepted as characteristic of 5-HT3 receptors, (150) by acting on a receptor that may be of the 5-HT7 nondesensitizing responses have also been reported. This shift is mediated by stimulation of ade- sal root ganglion cells, a relatively rapid but noninactivating nylate cyclase because it is mimicked by increasing intracel- depolarizing response has been described that has a 5-HT3 lular cyclic adenosine monophosphate (cAMP) and blocked pharmacologic profile (140). In neurons of nucleus tractus by inhibiting protein kinase A (151). However, the precise solitarius brain slices, a postsynaptic depolarizing response mechanism by which 5-HT7 receptors act is not presently to 5-HT3 agonists has been observed that is not rapidly known because it is unclear whether suprachiasmatic neu- desensitizing (141). In addition to these postsynaptic effects, rons themselves express the 5-HT7 receptors (144). Further- a 5-HT receptor-mediated increase in Ca2 influx has more, the effect of 5-HT on the membrane properties of 3 been described in a subpopulation of striatal nerve terminals these cells has not been examined. Another electrophysiologic effect that may be mediated The first known protein G -coupleds 5-HT receptor, the 5- through 5-HT receptors that are positively coupled to ade- HT4 receptor, was identified on the basis of pharmacologic nylate cyclase is the enhancement of the hyperpolarizing- and biochemical criteria (e. The Ih channels, responses to adenylyl cyclase) (9). Subsequently, a receptor which are homologous to cyclic nucleotide-gated channels with matching pharmacologic and other properties was in specialized sensory neurons, are positively modulated by cloned and found to be expressed in various regions of the cAMP (153,154). An increase in Ih tends to prevent exces- brain (143). Two other 5-HT receptors positively coupled sive hyperpolarization and increase neuronal excitability. Because their pharma- a number of regions of the brain, including the thalamus cology differed from that of the previously described 5-HT4 (155), prepositus hypoglossi (156), substantia nigra zona site, they were designated as 5-HT6 and 5-HT7 receptors compacta (157), and hippocampus (158), 5-HT has been (144–146). At this time, electrophysiologic studies are avail- shown to enhance Ih through a cAMP-dependent mecha- able only for the 5-HT4 and 5-HT7 receptors and are de- nism. Results of a pharmacologic analysis with multiple scribed below. Recently, the first drug with selectivity Binding studies using a selective 5-HT4 ligand indicate that toward the 5-HT7 receptor was shown to block activation 5-HT4 receptors are present in several discrete regions of of adenylyl cyclase by 5-HT agonists in guinea pig hippo- the mammalian brain, including the striatum, substantia campus (33). The increasing availability of such selective nigra, olfactory tubercle, and hippocampus (147). Because drugs should greatly enhance the electrophysiologic evalua- these regions also express 5-HT4-receptor mRNA, it appears tion of G -coupleds 5-HT receptors. The best studied of these regions is the hippocampus, in which both biochemical and electro- INTRACELLULAR SIGNAL TRANSDUCTION physiologic studies have provided a detailed picture of the PATHWAYS actions of 5-HT at 5-HT4 receptors. Electrophysiologic Multiple Signaling Pathways: G Proteins studies show that 5-HT4 receptors mediate an inhibition and Second Messengers of a calcium-activated potassium current that is responsible for the generation of a slow after-hyperpolarization in hip- Multiple intracellular signaling pathways constitute a com- pocampal pyramidal cells of the CA1 region (74,148,149). Inhibition of adenylate cyclase 24 Neuropsychopharmacology: The Fifth Generation of Progress was the first intracellular pathway to be described for campal homogenates suggests that both the 5-HT4 and 5- Gi/o protein-coupled receptors, such as the 5-HT1A recep- HT7 receptors are involved in cAMP formation (adenylate tor. However, it is now clear that these receptors regulate cyclase isoform unknown) in the hippocampus (164). Inter- multiple signaling pathways and effector molecules (Fig. Although all these signals are sensitive to pertussis G11,G14, and G15/16) activate phospholipase C in a pertussis toxin, so that Gi/o proteins are implicated, they may be toxin-insensitive manner. Activation of phospholipase C mediated by distinct G protein complexes. For example, was the first signal transduction mechanism identified for coupling to GIRK channels is mediated by subunits the 5-HT2-receptor family and is essentially universal. This released from Gi (and possibly Go) proteins, whereas inhibi- probably reflects the wide distribution of G and the 2 q/11 tion of Ca channels is mediated by subunits released functional redundancy of these two G proteins. The profile of signaling molecules varies HT receptor has been shown to couple in a pertussis 2C from cell to cell, offering diverse signaling possibilities and toxin-sensitive manner to G in Xenopus oocytes (e. In con- receptor activation of phospholipase C is cell-type depen- trast, recent evidence suggests that phospholipase C activa- dent; this signal is mediated by G protein subunits and tion in a native setting (choroid plexus) is mediated entirely thus requires the presence of a -regulated phospholipase by G coupling (167). The subunits, generated by dissociation of to G with subsequent cytoskeletal rearrangement has been 13 the heterotrimeric Gi protein, also activate the type 2 iso- recently described in a transfected cell line (168). This activation is conditional, evidence suggests that 5-HT2A and 5-HT2C receptors cou- dependent on the coactivation by G s (i. Phospholipase A2 is a well-characterized inde- ing actions of G i and G do not offset each other. The pendent signal transduction pathway that leads to arachi- answer may lie in the details. In addition to the large family donic acid, with subsequent prostaglandin and leukotriene of G proteins (21 subunits, 5 subunits, and 11 sub- formation (169). Most of these in vascular smooth muscle and is also thought to be inde- molecules are found in the central nervous system. The G pendent of phospholipase C activation (170,171). The 5- protein that contributes activation of type 2 adenylate HT2Areceptor increases phospholipase D activity via a small cyclase is G i1 or G i2 heterotrimer (160), whereas all three G-protein ARF (adenosine diphosphate ribosylation factor) G i subunits ( i3 i2 i1) have the ability to inhibit pathway, with protein kinase C activation being the princi- adenylate cyclase types 5 and 6 (161). This type brain-derived neurotrophic factor expression in hippocam- of interaction has been shown to occur in brain, in which pus (173,174). In addition, a 5-HT2A receptor-mediated G -linkedi receptors enhance -adrenergic responses (162); increase in transforming growth factor- 1, secondary to a similar interaction may take place in cells that coexpress a 5-HT receptor family member with one of the 5-HT protein kinase C activation, has been described (175).
The PDF version of the complete edition discount tenormin 50mg on-line arteria 60, which was freely available th as of 14 July buy 50 mg tenormin with visa blood pressure names, was retrieved more than 5000 times in 6 months order tenormin 100 mg with amex blood pressure 70 over 50. Some chapters (Acute HIV infection generic tenormin 100mg line zytiga arrhythmia, HIV Testing) were read 10 times more often on a computer monitor than in a book. Flying Publisher By the end of the year 2004, the PDF version of HIV Medicine 2003 had been downloaded from our servers more than 24,000 times The chapters “Acute HIV Infection” and “HIV Therapy” had an additional 25,000 and 13,000 readers, respectively (see Table 1. A novelty with HIV Medicine 2003 was the copyright removal (http://hivmedicine. The simultaneous message to colleagues all over the world was “Colleagues, translate HIV Medicine 2003 and publicise the translation. If you want, you can even publish it under your own name. SARS Reference SARS Reference appeared between May and October 2003 in three th editions (www. The reader figures up to 5 May 2005 have been compiled in Table 1. The PDF documents of the three editions were accessed more than 50,000 times; the most important chapters were opened more than 30,000 times each. As in the case of HIV Medicine 2003, we removed the copyright for SARS Reference. The book was then translated into Chinese, French, Italian, Portuguese, Romanian, Spanish and Vietnamese (see http://sarsreference. The two Chinese translations were also published as printed booklets and handed out to 7,000 and 10,000 Chinese doctors, respectively, at the peak of the SARS epidemic (see Fig. SARS Reference had more than 200,000 readers in 20 months, because it was free of charge. It was translated into 8 languages because it was free of charge and the copyright had been removed. SARS Reference is in third place on the Google list after the CDC and the WHO, because it is known throughout the world. SARS Reference was reviewed twice, in Science and in the British Medical Journal (Page 70), because it showed new ways of publishing medical information. The decision has been made: we are going to write a medical textbook and publish it both as a book and on the internet. But how precisely do we set about approaching this project? Do we have the publishing skills to achieve success? In the last few years, doctors have seen how amazingly self-sufficient they have become in spreading medical 15 1. Whether we wanted to or not, we have all become experts in word processing. Think back: how many doctors were familiar with the layout of letters on a typewriter 20 years ago? Better still: we are not only adept at word processing but have also become practised layout designers. Anyone who has published scientific articles in medical journals has learned that he must “format” his texts in accordance with strict regulations. After all, the work performed in the medical publishing houses must be reduced to a minimum. What is left for medical publishing houses to do in this context? We type, our word-processing software typesets, PDF prints and the Internet distributes the online version. The only problem left would be distribution, which – as we will see later on – is a problem which can be solved for medical textbooks, 90% of which are sold in a relatively small number of specialised bookstores. So, let us put the question more precisely: what do we do if we have a finished manuscript? Do we go to a traditional publishing house or is it more beneficial to produce the book in our own garage? There is sometimes a sense of shame at the idea of publishing a written text ourselves. The argument: publishing houses are seen as a supervisory body, and it is this supervision that awards our texts the seal of approval, sanctifies our work, and renders sacred our Opus urbi et orbi. This was not true in the past – and is even less so today. In the medical publishing houses, more and more doctors are being replaced with economists. This may make sense within the business, but are economists the right people for us to talk to? Secondly, some medical publishing houses have suffered from globalisation, philosophy of efficiency and lean production structures. In the past, bestsellers existed to bring in enough money to help finance books which were not highly profitable but represented a meaningful supplement to the range. The tendency today, not surprisingly, is to avoid having to keep any exotic types on the payroll if at all possible, and to play safe and secure the financing of a new title right from the start by selling part of an edition to a pharmaceutical company. Thirdly, and this is perhaps the saddest point for doctors: morals are becoming rougher, the rules of courtesy are sinking into oblivion. Flying Publisher generation ago, old people say, courtesy and reserve ruled over any contact between doctors and publishers. In the age of rapid production, the doctor is becoming a supplier of raw material, has to meet delivery deadlines more than ever and is treated the way many people tend to treat delivery men: rudely. But to come back to the point mentioned at the beginning, that publishers are an important supervisory factor for the quality of our texts. In principle, supervisory bodies make sense, but are publishers the right ones for the job? Furthermore, which member of a medical publishing house should have been allowed to decide at the beginning of May 2003 – when even the specialists had only been aware of the extent of the SARS epidemic for six weeks – whether it was a sensible move to publish SARS Reference or not? Who has the right to decide whether something written by someone who has been practising his profession for 20 or 30 years should be published? The short-term image boost is stronger if your book is published by an established publishing house. The arguments that go against an author having a contract with a traditional publisher are: as a rule, you have to cede the rights to your own text; it is seldom possible today to persuade publishers to present a free parallel publication of the text on the internet; producing your own book can be considerably more lucrative. Thus, the following speak in favour of publishing your medical textbook by yourself: 1. The better establishment of your textbook in the long-term, since the parallel publication of a text both as a book and an internet version is still rare today. This gives you a selective advantage over authors who continue to publish their texts as books only. And of course, most important of all: you keep hold of the power.
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Photomicrographshowing dense innervationof the include the nucleus paragigantocellularis (PGi) and the ven- locus ceruleus (LC) by hypocretin/orexin Fibers purchase tenormin 50mg otc blood pressure wrist band. Low-power (A) tromedial aspect of the prepositus hypoglossi (PrH) in the and high-power (B) photographs of frontal sections through the rostroventrolateral and dorsomedial medulla buy 100 mg tenormin free shipping high blood pressure quiz, respectively rat LC after staining with antibodies for hypocretin and tyrosine hydroxylase(TH) order 100 mg tenormin amex arteria hepatica communis. These nuclei provide strong excitatory and inhibitory hypocretin fibers and brown TH-positive NE somata and den- influences on LCneurons buy discount tenormin 100mg on line arteria circumflexa scapulae, respectively, and are also sources drites. Strong hypo- of several neurotransmitter inputs to the LCnucleus (see cretin (orexin) innervation of the locus coeruleus activates noradrenergic cells. However, as previously stated, LCdendrites permission. Studies of inputs to these peri-LCdendritic zones indicate several additional possible strong inputs to LCneurons, including of another gene that makes hypocretin itself (27), produced the periaqueductal gray, medial preoptic nucleus, prefrontal narcolepsy symptoms in animals. This finding supports the cortex, and hypothalamus (4,8). Recent work has confirmed long-standing belief that the LCsystem is important in some of the proposed inputs, showing direct contacts onto sleep–waking processes (28) and indicates that sleep disor- peri-LCdendrites from amygdala (9) and nucleus tractus ders may involve anomalies in this hypocretin projection to solitarius (NTS) (10). These findings also offer a novel target for pharma- some of the other possible inputs to LCdistal dendrites. Stimulation of the PGi strongly excites been found in LCafferents (see ref. The PGi has strong autonomic functions, sources of some of these inputs have been determined. These findings, in the PGi, -aminobutyric acid (GABA) inputs arise from together with the strong cortical projections of LCneurons, the PrH (13), and strong enkephalin projections to the LC suggest that the LCacts as a cognitive component of a global originate in both the PGi and the PrH (14). In contrast, strong inhibition is pro- fibers innervate the LC, presumably originating in the tub- duced by PrH stimulation (13); the functional significance eromammillary nucleus (15). A particularly dense innerva- of this input is unclear. 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. Ultrastructural analyses have mate input is antagonized pharmacologically (30). Inputs shown that several of these inputs directly innervate LC to distal LCdendrites from the amygdala (9) or NTS (10) neurons (16–20). 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. Upper: Post-stimulus time histograms (PSTHs) for LC activity during the visual discrimi- nation task. B,D: Poor behavioral performance (false alarm rate typically 7%; tonic LC mode). All histograms are normalized to a standard of 100 trials. Note that the phasic LC mode is found during periods of good performance, and that the tonic mode corresponds to A,B poor performance on this task. These simulation PSTHs are normalized for 100 trials, as for the empiric data. Note that coupling reduces tonic (baseline) LC activity but in- creases phasic (transient) response to target stimuli, captur- ing the phasic mode of LC neurons in our recordings. The role of locus coeruleus in the regulation of cognitive performance. First, they support the view that the LChas an important role in attentional processes, and that pathol- ogy in LCfunction could contribute to mental disorders with attentional components [e.
