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In addition best tenormin 50 mg arrhythmias definition, there will be many species represented on the not-too-distant future. Meanwhile, experiments can be big arrays, the actions of which are unknown. These have between task will be to assign them functions (see below). Consider, for example, the work that could be data have developed quickly. In spite of this, the supply of done to understand the mechanism(s) of action of selective arrays has not kept up with demand, and demand should serotonin reuptake inhibitors (SSRIs) and the reason for increase dramatically if the goal of using arrays is to compare their delayed onset of action in depressed patients. As is many conditions and then mine the data systematically for known, SSRIs increase the availability of serotonin (5-hy- patterns of gene expression. Thus, as stated earlier, costly droxytryptamine, 5-HT) to presynaptic and postsynaptic products are unlikely to gain wide acceptance, and glass receptors, of which there are at least 14 subtypes (50). For Among these, 5-HT1A receptors on serotoninergic raphe this reason, I now discuss their production and use. Some sets of cDNAs have been se- anxiety, inhibit serotonin secretion. Conversely, desensitiza- quence verified and are ideal to use for preparing arrays; tion of 5-HT1A receptors, which could result from elevated others have not been validated and are less useful. To make 5-HT levels in the synaptic space following SSRI adminis- arrays, plasmid DNA is prepared from gridded sets of clones tration, may have the opposite effect—an increase in 5-HT to be printed, and (typically) the 3′ end of each cDNA is release by raphe neurons, and chronic stimulation of 5-HT amplified by PCR. The purified PCR products are then receptors in regions such as the hippocampus, amygdala, spotted using a robotic arrayer. Many thousands of 100- M spots type I and type II (42). In the former, two samples are can be printed on a single glass microscope slide (see ref. This is because the relationship between be labeled with a different fluorescent dye that could, in the amount of transcript in a mixture and the intensity of turn, be visualized with a different laser. Presently, most the fluorescent spot it produces is a complex one—in- commercial readers have only two lasers, but four-color in- fluenced by labeling efficiency, hybridization and wash con- struments have already appeared on the market. To achieve this goal, in a two-sample experi- duces. Pools of cell-line RNAs have been used as standards mined for each spot, and the relative abundance of the two for human work. It would be useful if a central source of input RNAs can then be estimated. NORMALIZING RATIOS Since it is difficult, if not impossible, to measure the amount of RNA used to produce a labeled probe, normalizing the signals from the source RNAs is essential. The housekeeping set needs to be defined empirically, and in looking for candi- dates to include in such a set, few genes have been found that have constant expression levels. When small arrays are employed, on the other hand, the size and composition of the gene set used for normaliza- tion are very important. Just as a reference standard is ur- gently needed now, a normalization set supplied by a central site would be quite valuable. To perform microarray experiments, RNA is puri- fied from two or more samples of cultured cells or dissected tis- QUALITY CONTROL sues. Inthe exam- ple given, the dye cy5, which fluoresces red, was used to label probe from sample 1; and the dye cy3, which fluoresces green, While we have methods to assess the quality of DNA se- was used to label probe from sample 2. The labeled products are quence data, for example, there is no generally accepted mixed and hybridized to the spots on the microarray. Following a wash step, the array is scanned and the signals from the red method for establishing the quality of an array study. If an RNA species is more spite of this, there are some controls that can be built into abundant in sample 1than 2, the resulting spot will be red; in an array. As noted earlier, scientists are arraying DNAs gen- the reverse case, the spot will be green. When the RNA is equally abundant in the two samples, the spot is yellow. See color version erated by PCR from plasmid templates. Amplifying these with 294 Neuropsychopharmacology: The Fifth Generation of Progress Over time, the methods used to make and probe arrays should improve, and false negatives will grow less important.
Direct cost structure uncertainty refers to the separate uncertainty about data (hospitalization tenormin 100mg with visa blood pressure cuff walgreens, medication, physician visits, and labo- the manner in which parameters should properly be com- ratory tests) and the efficacy data from the model were en- bined (e. The decision tree analysis pro- fects additive or multiplicative? An approach to evaluation vided estimates of the expected cost of treatment per Chapter 39: The Role of Pharmaceuticals in Mental Health Care Outcomes 531 depressive episode that could be used by the health service terns of care experienced by most patients. As a result, real-world effects can be Data Sources difficult to extrapolate from ordinary clinical trials. This Data for pharmaceutical outcomes studies can come from issue is discussed further below. Many pharmaceutical companies routinely differentiate the SSRIs and TCAs, except for their side- include pharmaceutical outcome (other than just clinical) effect profiles. However, SSRIs may have some advantage measurements in their development trials. In addition, post- over TCAs in the primary care practice setting (6,28,29). Each of these sources of data ceutical outcomes of interest for a given product are expen- and type of experimentation affect the degree of evidence sive, and data collection of all relevant information is diffi- obtained. Therefore, many pharmaceutical outcome studies mental health care requires careful consideration of the contribute to the body of knowledge by evaluating compo- source and strength of the evidence presented. Additionally, many pharmaco- economic analyses are based on models. These models typi- cally use published literature, expert opinion, or data from HUMANISTIC MEASURES administrative or encounter databases to get information on probabilities and costs. Humanistic measures assess how disease or treatment affects The impact of this component approach to building an patients. Humanistic measures are most important from the understanding of pharmaceutical outcomes is that data perspective of the patient. A primary goal for treatment of come from many sources ranging from experimental and any disease should be for patients to function normally, nonexperimental research designs to expert opinion and have an acceptable quality of life, and be satisfied with their models based on data from multiple and frequently diverse treatment. This is especially true for mental health disorders sources. Therefore, when reviewing pharmaceutical out- where impacts on both physical and social functioning may comes research, it is critical to understand the potential be significant. In many cases, patients and their friends and impact of the source of information on the results. Until A frequent source of outcomes data in mental health recently, humanistic measures have taken a back seat to research is randomized clinical trials conducted by the phar- traditional clinical measures and to some extent economic maceutical industry. This is in part due to greater variability from controlled and typically contain (as expected) mostly clinical patient self-reported measures compared to standard clinical information. In mental health, however, patient self-re- measures (34). The development of valid and reliable instru- ported items (i. There are also many studies that rely on chart review mon conceptualization of humanistic outcomes used in the and quasi-experimentation to document differences in re- evaluation of pharmaceuticals is health-related quality of source use for patients using various pharmaceutical agents. Examples include recent comparisons of tricyclic antide- Health-related quality of life encompasses factors such pressants and SSRIs, and atypical versus conventional anti- as functional status, physiologic status, social and emotional psychotic agents. Many of these studies were retrospective well-being, and life satisfaction (35). Health-related quality and were conducted through chart reviews or administrative of life information allows health care providers and payers data using quasi-experimental techniques. Finally, eco- to make decisions based not only on clinical effectiveness, nomic models have been built using published data or expert or costs but also on effects that are important to patients. Measurement of health-related quality of life may be espe- Historically, randomized controlled trials have been the cially important in chronic diseases for which we have no 'gold standard' (5). There are many humanistic measures available for as- and safety of a drug to be established.
Co-localization of D(4) receptor localization in the rat nucleus accumbens shell order tenormin 100mg overnight delivery blood pressure 200 over 100. Alterations in electrophysiological activity via presynaptic D1-like dopamine receptors. J Neurosci 1996; and dye coupling of striatal spiny and aspiny neurons in dopa- 16:1591–604. Amphetamine withdrawal alters bistable in the rat nucleus accumbens via adenosine release. J Neurosci states and cellular coupling in rat prefrontal cortex and nucleus 1997;17:5271–5280. Repeated treatment with haloperidol and cleus accumbens is attenuated by the protein kinase C inhibitor clozapine exerts differential effects on dye coupling between Ro 32-0432. Unilateral dopamine 132 Neuropsychopharmacology: The Fifth Generation of Progress denervation blocks corticostriatal LTP. The metabolic pathways link- stasis and function as extracellular messengers to regulate ing ATP, ADP, AMP, and adenosine and the potential for cell function. The effects of adenosine and the nucleotides each of these purines to elicit distinct receptor-mediated are mediated by activation of distinct P1 (adenosine) and effects on cell function form the basis of a complex, physio- P2 (ATP) cell-surface receptors present on neurons, astro- logically relevant, purinergic cascade comparable to those cytes, and microglia, as well as other cells that are present involved blood clotting and complement activation (8) (Fig. These receptors are ge- The extracellular effects of ATP on the various members nerically known as purinergic receptors (1). Thus, functional activities, some of which are antagonistic to one the factors regulating their availability in the extracellular another. For instance, ATP antagonizes ADP actions on space as chemical messengers have been an area of active platelet aggregation, whereas adenosine-elicited CNS seda- research and considerable debate since the late 1970s (2). In the broader framework of ATP-modulated pro- acetylcholine, norepinephrine, glutamate, -aminobutyric teins (or ATP-binding cassette proteins), ATP-sensitive po- acid (GABA), calcitonin gene–related peptide, vasoactive tassium channels (KATP) undergo activation when intra- intestinal peptide, and neuropeptide Y (3). ATP is available cellular ATP levels are reduced (10,11). Thus, as P2 on demand, and the body can synthesize its own weight in receptor–mediated responses decrease because of ATP hy- ATP per day (4). Even though extracellular ATP levels can drolysis to adenosine, P1-mediated responses and KATP-me- reach millimolar concentrations in the extracellular local diated responses are enhanced. In addition to activating the environment after release or cellular perturbation (1), these as yet uncloned platelet P2T receptor, ADP also enhances concentrations are miniscule compared with the overall its own availability. Activation of A1 and A2A receptors can steady-state nucleotide content of the cell. Once released, inhibit ATP availability (1), and activation of hippocampal in addition to interacting directly with P2 receptors, ATP A2A and A3 receptors can desensitize A1 receptor–mediated can be hydrolyzed by a family of approximately 11 ecto- inhibition of excitatory neurotransmission (12). The trans- nucleotidases that metabolize ATP, ADP, diadenosine poly- fer of purines transfer from one cell to another in the context phosphates such as Ap4A, Ap5A (Fig. Ecto-ATPases hydrolyze which purines can modulate cellular communication, in ATP to ADP, ectoapyrases convert both ATP and ADP to terms of both information transfer and alteration of the AMP, and ecto-5′-nucleotidase converts AMP to adenosine. ATP also functions as a substrate for The activities of ectoapyrase and ecto-5′-nucleotidase can synaptic ectokinases, which modulate the phosphorylation state of the synaptic membrane (14) and, consequently, the intrinsic properties of the synapse. Once in the extracellular Michael Williams: Department of Molecular Pharmacology and Biologi- space, ATP thus has the ability to function as a pluripotent cal Chemistry, Northwestern University School of Medicine, Chicago, Illinois. Structures of P1 and P2 agonists and modulators of adenosine availability. Chapter 15: Purinergic Neurotransmission 193 FIGURE 15. ATP is released into the extracellular mi- lieu from nerves or cells, where they can interact to form a purinergic cascade. ATP acts at a variety of P2 receptors (see text) and is sequentially degraded to ADP and AMP by ectonucleotidase activity. AMP gives rise to adenosine, which can interact with the various P1 receptors (A1,A2A,A2B,A). Adenylate charge indicates the transfer of energy in the form of adenine nucleosides or nu- cleotidesfromonecell toanother(seeref. Recombination of nAChR -sub- Extracellular adenosine levels at rest are in the range of units with P2X receptor subunits to form functional 30 to 300 nM (18), and they subserve a physiologic role receptor constructs has also been reported (24), a finding in tissue homeostasis as reflected by the CNS stimulant further suggesting that heterooligimerization between these actions of caffeine, a natural methylxanthine that acts as an two different classes of LGICs may occurs and represents antagonist to counteract the sedative actions of endogenous a molecular basis for the cross-talk hypothesis.
Taken together discount tenormin 50 mg free shipping heart attack japanese, in genetically modified mice (see CRH System Transgenic these findings suggest that in primates, a fearful endopheno- Mice). Studying dent strains, as a consequence of their distinct genetic make- species-specific defensive behaviors and their neuroendo- ups, display different baseline levels of gene expression crine and physiologic correlates offers a powerful approach within various systems that are known to regulate the for identifying animal correlates of anxiety. The study of various rodent strains may thus help to identify the neu- Rodents rogenetic differences that contribute to individual differ- Extreme individual differences in the expression of stress- ences in stress susceptibility, and thereby further character- related defensive behaviors have also been noted in rodent ize the interaction between genes and environmental 888 Neuropsychopharmacology: The Fifth Generation of Progress conditions in the etiology of anxiety. Although such infor- are produced as a result of separating infants from their mation is useful, it remains to be determined whether or mothers prior to weaning. The notion that perturbations not the specific genetic differences identified above actually in the early postnatal environment might have enduring underlie the different behavioral effects. It is probable that neuroendocrine, neurochemical, and behavioral effects was a number of genes in addition to those described above originally put forth several decades ago by Levine (58). It are differentially expressed across different rodent strains. Future studies in which behavioral phe- notypes are assessed after the application of novel gene tar- The classic studies by Harlow and colleagues (20,61,62) of geting techniques to selectively disrupt or restore gene func- the effects of maternal separation in primates found that in tion in these rodent strains will aid in clarifying these issues. During the first months of life, the MATERNAL DEPRIVATION: AN attachment between mother and infant is intense, and as a ENVIRONMENTAL MANIPULATION THAT consequence the infant remains in close proximity to its CAN LEAD TO FEARFUL ENDOPHENOTYPES mother (61,63). Long-term maternal separation can result IN PRIMATES AND RODENTS in profound alterations in stress-related behavioral responses in the separated offspring. Monkeys that have been sepa- Converging lines of evidence from a number of species point rated from their mothers for prolonged periods during this to the importance of the early postnatal period, and in par- time exhibit symptoms of enhanced defensive or fear-related ticular the bond between mother and infant, in the develop- behavioral responses into adulthood and appear socially ment of normal defensive behaviors and the putative emo- withdrawn, a phenomenon that has led to the suggestion tional states underlying these behaviors. It has been observed that the behavioral and neuroendocrine sequelae of maternal that children who were placed in nurseries that lacked ade- separation might provide a model for some of the dysfunc- quate social stimulation developed a syndrome of 'protest, tion that is observed in anxiety disorders and depression despair, and detachment' that may be analogous to an in- (64–68). Cortisol has been found to play the early development of mammals is the interaction be- an important role in mediating the development of defen- tween the infant and its mother. As described above, separa- sive responses (69); thus, factors that were expected to affect tion of an infant from its mother during this early develop- infant primate cortisol concentrations were examined. It mental phase represents a significant stressor that markedly was found that maternal cortisol levels were moderately cor- and negatively affects the subsequent emotional develop- related with those of their infants (38). In fact, disruption of normal also found that maternal parity was negatively correlated attachment behavior at critical developmental phases can, with infant cortisol levels such that the current infants of in a number of species, lead to marked and persistent distur- mothers that previously had more offspring were likely to bances in behaviors and brain systems that are thought to have lower cortisol levels. Although the precise mechanism for this interaction identifying an environmental manipulation that can be used remains to be determined, it is likely that mothers with to create animal models of increased stress-related function- little rearing experience would interact differently with their ing. Indeed, a large body of work in monkeys and rats indi- infants than mothers with more experience. Coplan and col- nursing and contacting the offspring is not affected, but leagues (70,71) found that CSFlevels of CRH are basally rather the quality of the interaction between mother and and chronically elevated in adult bonnet macaques whose pup is altered. In nonseparated pups, individual differences mothers were exposed for 3 months to an unpredictable in LG-ABN predict hypothalamic-pituitary-adrenal (HPA) variable foraging demand (VFD), in comparison to mothers axis responsivity in adulthood such that mothers that engage confronted with either a high but predictable or low but in high levels of LG-ABN have offspring that, as adults, predictable foraging demand. Infants reared by VFD-ex- show reduced HPA axis activation in response to stress and posed mothers have been found to subsequently display ab- have decreased levels of CRH mRNA in the paraventricular normal affiliative social behaviors in adulthood (72). Pups that are findings are consistent with the recent results from this lab born to mothers that naturally exhibit high levels of LG- that indicate that CSFCRH levels are elevated in disposi- ABN grow up into adults that display low-anxiety–like be- tionally fearful monkeys, and that this CRH elevation is a haviors (increased exploration of novel environments) and stable trait-like characteristic of fearful endophenotype (5). Taken Rats together, these findings indicate that increased nurturing These aforementioned findings in nonhuman primates sup- physical contact from the mother can lead to a toned-down port the notion that mother-infant interactions may be a stress-responsive system in the offspring. Maternal separation has also been found to have the opposite effect on stress-related functioning later to produce long-term changes in defensive behaviors into in life. Rat pups that are separated from the mother for 3 adulthood in rats. Using the maternal separation paradigm hours or longer (investigators have often used a 24-hour in rats, investigators have also been able to begin to elucidate separation) show in adulthood increased CRH system gene some of the alterations in gene expression that take place expression, exaggerated HPA axis responses to stress, and in response to this early life stressor. Other intense stressors such as direction of the long-term changes, as has been reviewed in an endotoxin insult during the perinatal stage are also able detail recently (73–75). Thus, brief periods of separation to produce marked elevations in basal CRH gene expression (3 to 15 minutes per bout, once a day, for roughly 2 weeks) and lead to an exaggerated stress-induced HPA axis response from the mother result in a profile indicative of diminished in adulthood (81).
