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A number of items make up each category to provide a total score from 16 NIHR Journals Library www order fildena 100mg with mastercard. Questionnaire items generic fildena 50 mg without prescription, the scoring system and the tolerances for missing data can be seen in Appendix 2 discount 50 mg fildena free shipping. Children completed the FIQ twice best fildena 100 mg, at baseline and at 18 months, to allow the assessment of weekday (completed Tuesday to Friday) and weekend (completed on a Monday) food intake. The HeLP co-ordinator led the two lessons required for the children to complete the questionnaires at each time point. Children were arranged in literacy tables to ensure that assistance could be given as efficiently as possible. Support was also provided by an additional researcher, the class teacher and the teaching assistant. My Lifestyle Questionnaire The MLQ was designed to assess knowledge and a series of potential cognitive and behavioural mediators of any observed differences in outcome between the control and the intervention groups. The questionnaire included items designed to assess knowledge, self-efficacy, intentions, peer norms, family approval, attitudes towards restrictions on behaviour, parental provision and rules, goal-setting, self-monitoring and a range of relevant behavioural skills, including suggestions to and discussion with parents, shopping, cooking and trying new snacks. These items were derived from previous research applying the IMB and health action process models but tailored to the logic model underpinning the development of HeLP (see Appendix 3). School assessment Information on the school-level characteristics and policies on physical activity and nutrition adopted in each school was collected at baseline (October/November 2012/13) and at 18 months (June/July 2014/15) (see Appendix 4) using a questionnaire that was completed by a member of staff and/or an administrator. Index of Multiple Deprivation The Index of Multiple Deprivation (IMD) score was assigned to the lower super output area of each school and pupil as determined by their postcode. Changes to trial protocol There were two substantial amendments to the protocol during the course of the trial. The first amendment was to clarify the inclusion criteria to include schools who had one single Year 5 class but who may have had a second class that mixed Year 5 and Year 6 children. The second amendment related to schools allocated to cohort 2 of the study, which were due to start the study in September 2013 (cohort 1 schools started in September 2012). These schools were re-contacted in July 2013, at which time two indicated that their circumstances had changed and that they were no longer able (or eligible) to participate in the trial. Schools that had been placed on the waiting list were then contacted to establish if they were still willing and eligible to participate, of which two were. Given the possibility of selection bias in the two withdrawn schools and in terms of potential imbalance between intervention and control groups in school-level confounders (known and unknown), the 16 schools in cohort 2 (i. This was completed using a minimisation approach to ensure reasonable balance in the stratification factors between the allocated groups across the combined two cohorts. Statistical analysis A detailed analysis plan was developed by the Trial Management Group and approved by the TSC in November 2015. These amendments were approved by the TSC chairperson in September 2016. 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 17 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. TRIAL DESIGN AND METHODS plan and a summary of the amendments are published on the NIHR Public Health Research programme website, along with the study protocol. All comparative analyses allowed for the clustered nature of the data (i. Unless otherwise specified, all adjusted comparative analyses were adjusted for the two stratification variables (the proportion of children eligible for free school meals and the number of Year 5 classes) and baseline values for the outcome under consideration, when available. The analyses were also adjusted for gender and cohort. Between-group differences with only adjustment for clustering are presented for completeness. When given, p-values for statistical significance are two-sided and the significance level was set at ≤ 0. Adjustments were not made for multiple testing as the primary outcome of interest was clearly defined a priori. As this is a trial of a complex intervention, the secondary outcomes are all potentially of interest and relevance to participants, parents and other stakeholders. Interpretation of the clinical significance of any differences between the two groups acknowledges the range of variables being measured. Summaries of continuous/measurement variables comprise the number of schools or participants and either i. Summaries of categorical variables comprise the number of schools or participants and the number and percentage of observations in each category. Participating schools were compared with state primary schools in Devon and England at the time of school recruitment into the trial (2012) in terms of the following characteristics: l percentage of children eligible for free school meals l average number of pupils per school l percentage of children achieving level 4 at Key Stage 2 l proportion of pupils with English as an additional language. The recruitment, flow and follow-up of schools and children in the trial are summarised using the CONSORT-style flow diagram appropriate for cluster trials. The extent and distribution of missing data for each variable were assessed and dealt with as detailed in General methods, Missing outcome data. Data sources and data entry The data analysed came from a number of sources. Data collection for all sources followed standard operating procedures, as outlined in Study design, Outcome measures. Anthropometric measures were captured on a specifically designed data collection form. All data were entered twice, first by the data manager and then by another member of the research team, and stored on a secure purposively designed database. Data queries were raised and resolved at data entry. Data discrepancies following second data entry were discussed and resolved with the trial manager. Comparison of baseline characteristics Baseline characteristics were collected at the beginning of each cohort of the trial and appropriate summary statistics were computed to compare allocated groups for appropriate balance and to provide an overview of the study sample, at both school and child levels. At the child level, the characteristics included gender, age at baseline data collection, ethnicity, individual IMD value, all anthropometric measurements, physical activity and FIQ. The formal statistical comparison at baseline of randomised groups is not good practice46 and, thus, was not undertaken: only summary statistics are presented in Chapter 3. We prespecified that should there be any substantial imbalance between randomised groups at baseline, in terms of any relevant variables not already being adjusted for in the primary analysis, further adjusted sensitivity analyses may be performed, to allow for such variable(s), in addition to the prespecified variables for adjustment, to assess the robustness of the primary analysis. Adjusted analyses included the two school-level stratification variables as covariates, as well as baseline BMI SDS, gender and cohort. The means and SDs are presented for each group, together with the mean difference (intervention minus control) between groups, the 95% CI for the mean difference and the corresponding p-value. The ICC (with 95% CI) from the random-effects regression model for BMI SDS is also reported. Secondary analyses of the primary outcome A small number of sensitivity analyses of the primary outcome were prespecified in the analysis plan to assess how robust the results of the primary analyses were to any biases from missing data or to children in the intervention group who were categorised as non-compliers. These sensitivity analyses were revised following the TSC meeting in July 2016. The proposed amendments were approved by the TSC (chairperson) prior to undertaking the sensitivity analyses outlined below. Amendment 1 Given the low number of missing BMI scores and the low number of data deemed missing at random, a sensitivity analysis was undertaken to look at the effect of missing data using a best-case/worst-case scenario analysis. The first set of these analyses was based on hypothetically driven assumptions. Given the hypothetical preventative nature of the HeLP intervention, the best-case scenario: l assumed no change between baseline and 24 months in BMI SDS for children allocated to the intervention group (i. 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 19 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. TRIAL DESIGN AND METHODS The worst-case scenario: l assumed that children allocated to the intervention group who were not obese at baseline were obese at the 24 month follow-up: the 24 month BMI SDS value will be set at the Public Health England threshold for obesity (i.

Despite its frequent use purchase generic fildena on-line, heparin is rarely associated with overt hyperkalem ia; this suggests that other m echanism s (eg purchase fildena with paypal, reduced renal potassium secretion) m ust be present sim ultaneously for hyperkalem ia to m ani- fest itself cheap 25mg fildena mastercard. Both angiotensin-converting enzym e inhibitors and the angiotensin type 1 receptor blockers (AT1) receptor blockers interfere with adrenal aldosterone synthesis purchase fildena 150 mg visa. FIGURE 3-29 Approach to hyperkalem ia: pseudohypoaldosteronism. The m echa- nism of decreased potassium excretion is caused either by failure to secrete potassium in the cortical collecting tubule or enhanced reabsorption of potassium in the m edullary or papillary collecting tubules. Decreased secretion of potassium in the cortical and m edullary collecting duct results from decreases in either apical sodium or potassium channel function or dim inished basolateral N a+-K+-ATPase activity. Alternatively, potassium m ay be secreted norm ally but hyperkalem ia can develop because potassium reab- sorption is enhanced in the intercalated cells of the m edullary col- lecting duct (see Fig. The transtubule potassium gradient (TTKG) in both situations is inappropriately low and fails to nor- m alize in response to m ineralocorticoid replacem ent. This rare autosom ally transm itted disease is characterized by neonatal dehydration, failure to thrive, hyponatrem ia, hyper- kalem ia, and m etabolic acidosis. Kidney and adrenal function are norm al, and patients do not respond to exogenous m ineralocorti- coids. Genetic m utations responsible for PH A I occur in the and subunits of the am iloride-sensitive sodium channel of the collecting tubule. Fram eshift or prem ature stop codon m utations in the cyto- plasm ic am ino term inal or extracellular loop of either subunit dis- rupt the integrity of the sodium channel and result in loss of chan- nel activity. Failure to reabsorb sodium results in volum e depletion and activation of the renin-aldosterone axis. Furtherm ore, since sodium reabsorption is indirectly coupled to potassium and hydro- gen ion secretion, hyperkalem ia and m etabolic acidosis ensue. Hyperkalemia: Clinical M anifestations FIGURE 3-31 CLINICAL M ANIFESTATIONS OF HYPERKALEM IA Clinical m anifestations of hyperkalem ia. Cardiac Renal electrolyte Abnormal electrocardiogram Decreased renal NH4+ production Atrial/ventricular arrhythmias Natriuresis Pacemaker dysfunction Endocrine Neuromuscular Increased aldosterone secretion Paresthesias Increased insulin secretion Weakness Paralysis Diseases of Potassium M etabolism 3. B, Peaked, narrow-based T waves are the earliest sign of hyperkalem ia. C, The P wave broadens and the Q RS com plex widens when the plam sa potassium level is above 7 m Eq/L. D, W ith higher elevations in potassium , the P wave becom es difficult to identify. E, Eventually, an undulating sinu- soidal pattern is evident. Although the ECG changes are depicted here as correlating to the severity of hyperkalem ia, patients with even m ild ECG changes m ay abruptly progress to term inal rhythm disturbances. Thus, hyperkalem ia with any ECG changes should be treated as an em ergency. Hyperkalemia: Treatment FIGURE 3-33 Treatm ent of hyperkalem ia. Bia M J, DeFronzo RA: Extrarenal potassium hom eostasis. Arch Int M ed 1985, gene locus on chrom osom e 16q13 in a large kindred. Funder JW : Corticosteroid receptors and renal 11 -hydroxysteroid 7. M arriott H JL: M iscellaneous conditions: H ypokalem ia. Riem anschneider TH , Bohle A: M orphologic aspects of low-potassi- crossovers between CYP11B1 and CYP11B2. Proc N atl Acad Sci USA um and low-sodium nephropathy. Tolins JP, H ostetter M K, H ostetter TH : H ypokalem ic nephropathy in 9. In A Prim er on the rat: Role of am m onia in chronic tubular injury. DeFronzo RA: Regulation of extrarenal potassium hom eostasis by 19. In Current Topics in M em branes and the control of the plasm a potassium concentration. Kam el KS, Q uaggin S, Scheich A, H alperin M L: Disorders of potassi- 11. Giebisch G, W ang W : Potassium transport: from clearance to channels um hom eostasis: an approach based on pathophysiology. N ora N A, Berns AS: H ypokalem ic, hypophosphatem ic thyrotoxic concentration gradient in patients with hypokalem ia and hyper- periodic paralysis. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www. The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials that are clearly noted in the document. Further reproduction of those copyrighted materials is prohibited without the specific permission of copyright holders. Persons using assistive technology may not be able to fully access information in this report. None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report. Suggested citation: Al-Khatib SM, Allen Lapointe N, Chatterjee R, Crowley MJ, Dupre ME, Kong DF, Lopes RD, Povsic TJ, Raju SS, Shah BR, Kosinski A, McBroom AJ, Chobot MM, Gray R, Sanders GD. Rockville, MD: Agency for Healthcare Research and Quality; June 2013. These reviews provide comprehensive, science-based information on common, costly medical conditions, and new health care technologies and strategies. Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews can help clarify whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about AHRQ EPC systematic reviews, see www. Transparency and stakeholder input are essential to the Effective Health Care Program. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by email to epc@ahrq. Director Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Stephanie Chang, M. Director Task Order Officer Evidence-based Practice Program Center for Outcomes and Evidence Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality iii Acknowledgments The authors thank Connie Schardt, M. Key Informants In designing the study questions, the EPC consulted several Key Informants who represent the end-users of research. Key Informants are not involved in the analysis of the evidence or the writing of the report. Therefore, in the end, study questions, design, methodological approaches, and/or conclusions do not necessarily represent the views of individual Key Informants. Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest.

This extreme emotional response probably considered buy generic fildena canada. However purchase fildena 150mg free shipping, in PTSD fildena 100mg lowest price, recent review by Davidson and Slagter (59) buy fildena on line amex. A key issue this response is elicited in inappropriate situations. The pa- that is often neglected in the design of activation studies is tient with PTSD behaves like the animal with a hippocam- the specification of how deficits in the process that is being Chapter 28: The Neuronal Circuitry Underlying Mood and Anxiety Disorders 377 studied may account for the symptoms of the disorder. In this way, example, many of the early PET studies in patients with effects that may be specifically associated with the symptoms various types of psychopathology used easy continuous per- of the disorder can be disentangled from those associated formance tasks in which behavioral differences between with vulnerability to the disorder. The latter class of effects groups were not expected to occur, or they used unilateral may also arise as a consequence of scarring—effects pro- somatosensory stimulation (see ref. Just what the hypothesized relation was between designs that require subjects to be scanned and administered abnormalities in activation patterns in response to such tasks tasks on two or more occasions, it is imperative to have data and symptoms of the disorder being studied was most often on the test–retest stability of the effects in question. The better the concep- effects do not show stability over time, it becomes difficult tual link between task performance and symptomatology, to interpret group differences in change over time in task the more useful an activation paradigm will be for revealing activations. We have strongly advocated the psychometric the underlying deficits in the disorder in question. Several assessment of both psychophysiologic (64) and neuroimag- examples of strong conceptual connections between specific ing (65) measures. Such assessments can turn up important task-related deficits and symptomatology in both the cogni- surprises. Resting regional glucose metabolism measured tive and affective domains are available and can be consulted with PET is frequently used to assess baseline differences by the interested reader (see ref. Using MRI coregistration and regions of interest, we domain). One of the most found that all the regions we examined showed good important of these is matching the difficulty of an experi- test–retest stability, including the left and right hippocam- mental task with that of a control task. This is an issue with pus, left and right anterior caudate region, left and right a long history in experimental research in psychopathology thalamus, and the left amygdala, but not the right amygdala (62), although the neuroimaging field has yet to appreciate (65). The right amygdala apparently varied over time, in its significance fully. When performance on two tasks is part because metabolic rate in this region was more affected compared between groups, it is imperative that the difficulty by the stress of the first scan in comparison with activation of the two tasks be matched. When these pic- of differences in task difficulty and not specific to the pro- tures are used to compare patients and controls over time, cesses that are putatively required for performance of the it is again important to establish that the effects produced task. Chapman and Chapman (62) have provided many are stable over time in normal subjects. We used startle to examples of such artifactual group differences that are prod- probe the test–retest stability of the potentiation produced ucts of variation in task performance rather than reflections by negative pictures and the attenuation produced by posi- of differential deficit. It is therefore essential in neuroimag- tive pictures, and we found poor stability when the same ing studies for activation tasks to be matched in this way. It was only when If the tasks that are being compared in imaging studies are different pictures were used, matched on valence and arousal not matched, then any difference found in activation be- characteristics to the original set, that we found better stabil- tween tasks may arise as a consequence of differences in the ity (64). These data underscore the importance of not as- difficulty level of the tasks. Unfortunately, the neuroimag- suming that effects will be stable over time and the utility ing literature is replete with task comparisons for tasks that of actually measuring the test–retest stability of both task do indeed differ in the level of difficulty and thus are partic- performance and activation changes in normal subjects be- ularly problematic for comparisons between groups. The fore conducting a longitudinal study of changes in patients. In such as pleasant and unpleasant pictures, guided imagery, one of the few studies to have addressed this potential source monetary rewards and punishments, and symptom provoca- of confound, Barch et al. When such paradigms are used, it is function of specific task requirements when they compared imperative for the investigator to verify independently the such tasks to control tasks that were matched in level of presence of the intended affective state. Ideally, such verifi- difficulty but did not require working memory. For In studies with patients, investigators frequently wish to example, peripheral biological indices (e. Moreover, over, in this study, measures of brain electric activity paral- when such measures are used, correlations between activa- leled the performance data and revealed deficits in activation tions produced by the task in question and changes in the in the right posterior scalp. In more flow in the right amygdala during conditioning. Moreover, the magnitude of MR signal change in the amygdala predicts treatment response (55). Most of the extant imaging studies of patients with mood A unique strategy used in research on mood disorders disorders have been performed with PET while the subjects is the short-term depletion of tryptophan among remitted are in a baseline state. These findings have been recently depressed patients maintained on selective serotonin reup- reviewed elsewhere (68). The depletion of tryptophan, which reduces have reported associations between the severity of particular the presynaptic availability of serotonin, often results in de- symptom clusters and patterns of regional blood flow or pressive relapse. Thus, this method can be powerfully har- metabolism (69–71). These studies have underscored the nessed to examine activation patterns during the production importance of differentiating among various symptoms of of depressive relapse in mood-disordered patients. Bremner depression and illustrate the lawful relations that can be at al. When they com- toms and patterns of regional brain activity. The few studies pared subjects who showed a depletion-induced relapse in using activation paradigms that have been conducted in symptoms with those without relapse, they found that tryp- patients with mood disorders have utilized complex cogni- tophan depletion resulted in decreases in regional metabo- tive tasks designed to activate the PFC and ACC. Furthermore, patients who relapsed had a higher planning tasks during depressed mood in normal subjects baseline (i. Depressed subjects failed to show ing the dorsolateral PFC, orbitofrontal cortex, hippocam- normal task-related increases in blood flow in regions of the pus, and amygdala, than those who did not relapse, which PFC, ACC, basal ganglia, and thalamus. For example, Merriam et earlier in this article, is probably implemented at least in al. We have hypothesized that large group of patients with major depression who had been this form of positive affect is abnormally decreased in pa- without medication for at least 28 days. In riques and Davidson (77), using extremely carefully psycho- general, most studies that have used either symptom provo- metrically matched verbal and spatial tasks chosen to reflect cation or other procedures designed to activate the amygdala left- and right-sided posterior cortical function, found a se- have found greater activation in this region in response to Chapter 28: The Neuronal Circuitry Underlying Mood and Anxiety Disorders 379 such stimuli in anxious patients than in controls. For exam- to the underlying symptoms of the disorder should be made ple, in two studies using script-driven imagery and PET to explicit in this type of research. Several psychometric prob- assess regional blood flow, increased activation was found lems were then considered, including the issues of matching in the amygdala of patients with PTSD (84,85). In a more experimental and control tasks according to level of diffi- recent study comparing patients with PTSD and controls, culty and of establishing the reliability of tasks before using Rauch et al. Finally, in stud- expressions of fear versus masked expressions of happiness. It should be apparent from this anxiety disorders (e. In a series of studies that used despite its obvious importance in revealing the abnormali- PET to measure regional cerebral blood flow, Fredrikson ties in circuitry that underlie basic cognitive and affective and colleagues (88; see ref. It is imperative that the next generation of clinical in secondary visual associative regions in patients with snake investigators be trained in the methods and techniques of phobia in response to the presentation of phobia-relevant affective and cognitive neuroscience, the area where such visual stimuli (e. Interestingly, in a separate group of patients with It is also imperative that the results of burgeoning re- arachnophobia, this pattern did not change after the admin- search on cognitive and affective information-processing istrative of diazepam when the subjects were rescanned (90). For example, an extensive faces and aversive odor stimuli. The subjects in this study corpus of literature has now documented biases in forms of were all male; seven had been given a DSM-IV diagnosis explicit memory in depression and biases in attention in of social phobia and five were healthy controls matched for various types of anxiety disorders. Neutral faces, which do not lead to used to design activation paradigms that are more closely amygdala activation in nonpsychopathologic humans (92), linked to the various hypothesized underlying information- and aversive odors, which are significantly associated with processing deficits. Such research should help to uncover amygdala activation in comparison with a no-odorant con- abnormalities in the circuitry underlying the processing of trol condition (93), were presented to all the subjects. Bir- emotion and cognition in patients with mood and anxiety baumer et al. In both groups, odors elicited therapeutic approaches.

One of the prominent regulators of DA munication via its actions on gap junctions order fildena online now. It has been known for some time that DA neurons are very sensitive to DA can potently modulate its own dynamics proven 100mg fildena, acting via autore- agonists best purchase for fildena, which inhibit spike firing as well as cause a pre- ceptors on DA nerve terminals and on DA neuron somata fildena 100mg discount. Studies in- In fact, the DA system is under potent dynamic regulation dicate that DA neuron somatodendritic autoreceptors are in the short term by a multitude of feedback systems, and stimulated by an extracellular pool of DA released from the in response to prolonged alterations is subject to powerful dendrites of neighboring DA neurons rather than exclu- homeostatic mechanisms that can compensate for dramatic sively by autoinhibition back onto the releasing neuron. Such homeostatic altera- This is supported by data showing that partial lesions of tions can be compensatory in nature, such as those that the DA system result in DA autoreceptor supersensitivity occur in response to a partial DA system lesion, or patho- in the remaining neurons, which would only occur if the logic, such as the sensitization that can occur with repeated remaining neurons were responding to the decrease in DA psychostimulant administration. Nonetheless, the impor- caused by the loss of neighboring neurons (4). These autoreceptors appear to be ented toward increasing our understanding of this complex primarily of the D2 type, because D2-deficient mice do system in normal conditions as well as disease states. This not show autoreceptor-mediated inhibition of firing (6). This is not meant to be transferase does not alter this response (9). Exogenous transmitters also potently regulate dopamine inclusive: A search of Medline indicated that there were neurons. Thus, GABA afferents both from striatonigral neu- over 16,000 papers published on DA during the past 5 rons as well as from local circuit neurons in the midbrain years! Because of the exceedingly broad range that this topic cause inhibition of DA neuron activity (10) by both a encompasses, the focus is primarily on a subset of the nu- GABA-A– and GABA-B–mediated action (11–13). Gluta- merous improvements that are most related to advancing mate has also been shown to exert multiple actions on DA our understanding of psychiatric disorders in particular. Glutamate applied in vivo increases burst Topics related to specific disorders, such as drug abuse, firing (14). N-methyl-D-aspartate (NMDA) receptor acti- schizophrenia, and so on, are deferred to the appropriate vation mediates a slow excitatory postsynaptic potential chapters in this volume. This latter effect is apparently shared by muscarinic receptors, which Anthony A. Grace: Departments of Neuroscienceand Psychiatry, Univer- also depress both excitatory and inhibitory afferents, pre- sity of Pittsburgh, Pittsburgh, Pennsylvania. Thus, studies have shown that burst Afferent Input firing in DA neurons is associated with induction of c-fos The feedback systems between DA neurons and their post- and NG1-A in postsynaptic sites (19,20), and this response demonstrates a spatial and temporal specificity with respect synaptic targets appear to be quite complex, particularly in to brain region, genes activated, and cell phenotype. By analyzing a large number of retrograde and factor that is thought to regulate burst firing is the gluta- anterograde tracings, Haber and associates (32) found that matergic system. Several studies have shown that ionto- different striatal subdivisions are linked by overlapping feed- phoresis of glutamate onto DA neurons in vivo lead to burst back to DA neurons, in a manner that suggests an ascending firing (14), as do stimulation of glutamatergic afferents to spiral of regulation extending from the shell to the core to DA neurons (21,22); however, the evidence for glutamate the central striatum and finally to the dorsolateral striatum acting alone to induce burst firing in vitro is equivocal (23). As pointed out by Haber, such an anatomic ar- In contrast, evidence shows that burst firing can be induced rangement could account for the parallel psychomotor, af- in vitro by blockade of apamin-sensitive potassium channels fective, and cognitive disturbances seen in a variety of psy- that modulate a nifedipine-sensitive calcium conductance chiatric disorders. One source of glutamatergic input to ventral tegmen- The striatum provides a powerful feedback regulation tal area (VTA) DA neurons is proposed to arise from the of DA neuron firing. Thus, alterations in striatal activity prefrontal cortex (PFC) (25); however, recent studies (26, potently affect DA cell activity states. Striatal neuron activa- 27) show that the PFC input to the VTA innervates only tion is known to cause an activation of DA neuron firing the small proportion of VTA DA neurons that project to the (10,33). Moreover, single-pulse stimulation of the striatum PFC, providing a direct feedback loop, whereas the VTA- directly, or indirectly via activation of the PFC in rats, causes accumbens neurons innervated from the PFC are exclusively an inhibition/excitation response pattern (10,25). This rela- GABAergic neurons; therefore, it is unlikely that activation tionship can be altered by manipulation of second messen- of the PFC can induce increased DA levels in the accumbens ger systems in the striatum. One system in particular that by a direct projection to these neurons (28). On the other seems to affect striatal activation, leading to an alteration FIGURE 9. Studies using retrograde and anterograde tracers reveal that the feedback system between the mid- brain DA neurons and their striatal targets contains both reciprocal and feed-forward components. The shell of the accumbens (left) receives inputs from hippocampus, amyg- dala, and limbic cortex, and projects to both the ventral tegmental area (VTA) and dorsomedial substantia nigra DA neurons. The core receives afferent input from the orbital and medial prefrontal cor- tex (OMPFC); the afferent projection to the core from the medial substantia nigra (SN) then forms the first part of the spiral. The core in turn projects to more ventrodorsal SN regions; therefore, ventral striatal regions can modu- late the dopaminergic influence over more dorsal striatal regions via the spiraling midbrain-striatal-midbrain con- nections. The magnified insert shows a model of the recip- rocal versus feed-forward loops. The reciprocal compo- nent is proposed to (a) directly inhibit the DA neuron, whereas the feed-forward, nonreciprocal component ter- minates on a GABAergic interneuron; or (b) indirectly ex- cite the DA neuron by disinhibition. DL-PFC, dorsolateral prefrontal cortex; IC, internal capsule; S, shell; Snc, sub- stantia nigra, zona compacta; Snr, substantia nigra, zona reticulata; VTA, ventral tegmental area. Therefore, unlike acute exposure to stressful or noxious Increasing NO in the striatum by infusion of the substrate stimuli, chronic stress actually attenuates DA neuron base- for the synthetic enzyme nitric oxide synthetase (NOS), line activity. Such a decrease in baseline activity could enable coupled with striatal or cortical stimulation, was found to the system to show a magnified response to activating stim- increase the firing rate of striatal neuron DA neurons. This uli, thereby producing a sensitized DA response. In contrast, NOS inhibitors failed to affect REGULATION OF DA RELEASE baseline DA cell firing but did increase their response to stimulation (34); therefore, NO signaling in the striatum DA appears to be released by multiple factors within its facilitates DA neurotransmission by modulation of cortico- postsynaptic target; moreover, once it is released, there are striatal and striatonigral pathways. NO also appears to have several mechanisms that can modulate its site of action. In a role in regulating terminal DA release (see the following). Carbon fiber recordings, which plays a role both in acute behavioral responses and adapta- allow rapid measurement of DA overflow, show that stimu- tions to chronic stressful conditions. Although the nor- lation of DA axons causes rapid release of transmitter. More- adrenergic system has played a major role in these processes, over, the release varies with tissue content, with PFC show- recent evidence supports a role for the DA system as well. DA released by impulse differential increases in DA dynamics depending on the flow is then rapidly removed via the DA transporter, because brain regions involved. Thus, stressful stimuli tend to cause mice with knockouts of this transporter exhibit 300 times the largest increase in DA levels in the PFC region, with longer clearance half-life compared to controls (42). The markedly smaller changes in the limbic and dorsal striatal amount of DA released by impulses appears to depend on regions (35); however, this relationship is altered by lesions several factors. Previous volumes in the Generations of of different nuclei. Thus, stress causes release of DA in the Progress series have detailed how DA release can be modu- amygdala (36), and lesions of the amygdala tend to block lated by both synthesis- and release-modulating autorecep- stress-induced increases in PFC DA levels (37). It is becoming more evident that the PFC also affect this response. Studies in which the PFC heteroceptors also play a significant role in modulating DA DA innervation is lesioned show that subsequent stressors release (43). One is the DA that is released in a high-ampli- response (38). This suggests that PFC DA released in re- tude, brief pulsatile manner by means of action potentials, sponse to stress actually blunts the responsiveness of the and then is rapidly removed from the synaptic cleft via reup- subcortical limbic DA system. This has been termed the phasic component of DA of PFC DA levels were found to decrease the basal electro- release (44), and is believed to underlie most of the behav- physiologic activity of VTA DA neurons (39). The other is the level of basal DA levels in the accumbens are normal, one interpreta- DA present in the extrasynaptic space. This tonic DA exists tion is that the DA release system has adapted to the dimin- in very low concentrations; too low to stimulate intrasynap- ished DA neuron drive, allowing normal levels of DA trans- tic DA receptors, but of sufficient level to activate extrasy- mission to occur. However, if a stimulus then causes an naptic receptors, including DA terminal autoreceptors increase in DA neuron firing, the compensated release (thereby causing feedback-inhibition of phasic DA release) mechanism would produce an augmented response. It is this tonic DA the magnitude of increase in action potential-dependent DA compartment that is sampled by slower measures of DA release into the accumbens that occurs in response to a chal- dynamics, such as microdialysis. Recently, evidence has lenge may be augmented when the PFC DA response is been advanced to define what factors may contribute to the attenuated (39). Repeated stress also has important clinical implications Although studies suggest that neuronal impulse flow is with regard to the DA system and exacerbation of schizo- necessary for DA overflow in the striatum, there is substan- phrenia. A recent study examined how chronic stress in the tial evidence that the released DA can be controlled locally form of cold exposure affects the discharge of VTA DA by a number of factors. Thus, after exposing rats to cold, there was a 64% inputs increases DA release within the striatum, and evi- decrease in the number of spontaneously active DA neurons, dence suggests that this can occur via afferents to DA cell with no significant alteration in their average firing rate.