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Cells transfected with cytosolic PLA2 exhibited 10 greater AA release and cell death in response to oxidant exposure 0 than cells transfected with the vector or secretory PLA2 or not 0 trusted 2.5 ml xalatan symptoms vertigo. These results suggest that activation of cytosolic C [H2O2] cheap xalatan 2.5 ml mastercard medicine 0031, mmol PLA2 during oxidant injury contributes to cell injury and death. A, Time-dependent effects of antimycin A treatment on inhibitor II is CPP32/apopain inhibitor (DEVD-CHO). B, C, The effect of two capase suggest that caspases are activated after mitochondrial inhibition and inhibitors on antimycin A–induced DNA damage and cell death, respec- that caspases may contribute to antimycin A–induced DNA damage tively. Antimycin A is an inhibitor of mitochondrial electron transport. Fish EM , M olitoris BA: Alterations in epithelial polarity and the 10. Suzuki K, O hno S: Calcium activated neutral protease: Structure-func- pathogenesis of disease states. N owak G, Aleo M D, M organ JA, Schnellm ann RG: Recovery of cellu- Seyler 1995, 376:523. W aters SL, Sarang SS, W ang KKW , Schnellm ann RG: Calpains m edi- 4. Am J Pathol 1995, ate calcium and chloride influx during the late phase of cell injury. M onks TJ, Lau SS: Renal transport processes and glutathione conju- 13. W aters SL, W ong JK, Schnellm ann RG: Depletion of endoplasm ic gate–m ediated nephrotoxicity. W aters SL, M iller GW , Aleo M D, Schnellm ann RG: N eurosteroid J Biol Chem 1991, 266:18415. Sapirstein A, Spech RA, W itzgall R, Bonventre JV: Cytosolic phospho- protein) and a H SP70-like protein (m ortalin) are m ajor targets for lipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen perox- m odification during S-(1,1,2,2-tetrafluoroethyl)-L-cysteine–induced ide cytotoxicity in kidney epithelial cells. Groves CE, Lock EA, Schnellm ann RG: Role of lipid peroxidation in 16. Kaushal GP, Ueda N , Shah SV: Role of caspases (ICE/CED3 proteases) renal proxim al tubule cell death induced by haloalkene cysteine conju- in DN A dam age and cell death in response to a m itochondrial gates. Schnellm ann RG: Pathophysiology of nephrotoxic cell injury. Bush Hiroyuki Sakurai Ta t s u o Ts u k a m o t o Sanjay K. Nigam lthough ischemic acute renal failure (ARF) is likely the result of many different factors, much tubule injury can be traced back Ato a number of specific lesions that occur at the cellular level in ischemic polarized epithelial cells. At the onset of an ischemic insult, rapid and dramatic biochemical changes in the cellular environment occur, most notably perturbation of the intracellular levels of ATP and free calcium and increases in the levels of free radicals, which lead to alterations in structural and functional cellular components charac- teristic of renal epithelial cells [1–7]. These alterations include a loss of tight junction integrity, disruption of actin-based microfilaments, and loss of the apical basolateral polarity of epithelial cells. The result is loss of normal renal cell function [7–12]. After acute renal ischemia, the recovery of renal tubule function is critically dependent on reestablishment of the permeability barrier, which is crucial to proper functioning of epithelial tissues such as renal tubules. After ischemic injury the formation of a functional perme- ability barrier, and thus of functional renal tubules, is critically depen- C H A P T ER dent on the establishment of functional tight junctions. The tight junc- tion is an apically oriented structure that functions as both the “fence” that separates apical and basolateral plasma membrane domains and the major paracellular permeability barrier (gate). It is not yet clear how the kidney restores tight junction structure and function after ischemic injury. In fact, tight junction assembly under normal physio- logical conditions remains ill-understood; however, utilization of the 16 16. M atrix proteins and helped to elucidate some of the critical features of tight junction their integrin receptors may need to be resynthesized, along with bioassembly. In this model for tight junction reassembly, signal- growth factors and cytokines, all of which pass through the endo- ing events involving G proteins, protein kinase C, and calcium plasmic reticulum (ER). The rate-limiting events in the biosynthe- appear necessary for the reestablishment of tight junctions sis and assembly of these proteins occur in the ER and are cat- [13–19]. Tight junction injury and recovery, like that which alyzed by a set of ER-specific molecular chaperones, some of occurs after ischemia and reperfusion, has similarly been mod- which are homologs of the cytosolic heat-shock proteins. The eled by subjecting cultured renal epithelial cells to ATP deple- levels of mRNAs for these proteins may increase 10-fold or more tion (“chemical anoxia”) followed by repletion. W hile there are in the ischemic kidney, to keep up with the cellular need to syn- many similarities to the calcium switch, biochemical studies thesize and transport these new membrane proteins, as well as have recently revealed major differences, for example, in the secreted ones. If the ischemic insult is sufficiently severe, cell death and/or Thus, important insights into the basic and applied biology of detachment leads to loss of cells from the epithelium lining the tight junctions are likely to be forthcoming from further analy- kidney tubules.

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Moreover xalatan 2.5 ml with amex medicine ketorolac, behavioral lationships between the stress-related hormone cortisol or inhibition in childhood (based on retrospective self-reports) asymmetric frontal EEG activity and individual differences is highly associated with anxiety in adulthood (35) xalatan 2.5 ml sale treatment of scabies. Thus, in 28 mother- of the physiologic correlates that have been observed in ex- infant pairs, it was found that in both mothers and infants tremely inhibited children are elevated levels of the stress- freezing duration was significantly and positively correlated related hormone cortisol (36) and greater sympathetic with baseline (nonstressed) cortisol levels (38). In nonhuman primates, indi- are consistent with findings from human studies demon- vidual differences in defensive behaviors have been studied strating that extremely inhibited children have elevated lev- in an attempt to elucidate the neuroendocrine and neuro- els of salivary cortisol (36,37), and is also consistent with biological concomitants of extreme behavioral inhibition findings in rodents that corticosterone (the rodent analogue and to characterize a primate analogue of an anxiety-related of cortisol) is required for rat pups to develop the ability endophenotype. Marked individual differences among rhesus monkeys Extremely fearful monkeys (as identified by the HIP) have been noted with regard to the intensity of context- also exhibit characteristic EEG patterns. In adult humans, Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 887 asymmetric right frontal brain activity has been associated species. The examination of naturally occurring genetic with negative emotional responses (40). Our studies in rhe- variations with regard to stress reactivity may have impor- sus monkeys have demonstrated similarities in this measure tant implications for the elucidation of individual differ- between monkeys and humans (41). Thus, it has been found ences in sensitivity to stressful situations. One example of that dispositionally fearful monkeys have extreme right naturally occurring individual differences comes from the frontal brain activity, paralleling the pattern of extreme right study of different rodent strains with regard to their level of frontal activity in humans who suffer from anxiety-related stress-like behavioral responding to environmental stimuli. In addition, it was found that individual differ- Because of the important role of the CRH system in regulat- ences in asymmetric frontal activity in nonhuman primates ing defensive behaviors induced by stressful or threatening in the 4- to 8-Hz range are a stable characteristic of an situations, attention has been focused on identifying rat or animal (41,42). Furthermore, a significant positive correla- mouse strains that display differential stress reactivity and tion between relative right asymmetric frontal activity and different baseline levels of CRH gene expression. For exam- basal cortisol levels in 50 one-year-old animals was found. An extreme groups analysis re- fawn-hooded rats compared to either Sprague-Dawleys or vealed that extreme right compared to extreme left frontal Wistars (44,45). Fawn-hooded rats have also been reported animals had greater cortisol concentrations as well as in- to exhibit exaggerated behavioral responses to stress such as creased defensive responses, such as freezing and hostility. Strain differences, which right frontal animals continued to demonstrate elevated cor- essentially reflect differential genetic makeups, have also tisol levels at 3 years of age. These results are the first to link been found to influence the effects of acute environmental individual differences in asymmetric frontal activity with stressors on regulating CRH system gene expression. This finding is important be- the stress of whole-body restraint produces a much larger cause both factors have been independently associated with increase in CRH mRNA levels within the hypothalamus of fearful temperamental styles. Fisher rats than in Wistars or Sprague-Dawleys (46,47). It has recently been found that cerebrospinal fluid (CSF) Similarly, the spontaneously hypertensive and borderline levels of corticotropin-releasing hormone (CRH), a peptide hypertensive strains of rats have increased basal and stress- that mediates stress responses, are significantly elevated in induced levels of hypothalamic CRH mRNA compared to monkeys that display exaggerated defensive responses to the Wistar and Sprague-Dawley strains (48–50). As stated before, these extreme indi- In mice, it has been shown that the BALB/c strain is vidual differences in defensive behaviors are stable over time. Finally, when comparing avoidance of aversive areas in a light-dark transition test and monkeys with extreme right frontal activity (that display an open field (51,52). These mice also show high levels of exaggerated fearful responses) to those with extreme left neophobia (53). Recent genetic mapping studies in these frontal activity (that display low levels of fearful behaviors), strains have revealed that these behavioral differences may the right frontal group was found to consistently have in- be associated with differential levels of -aminobutyric acid creased CSFCRH levels over a period of 4 years (5). Thus, receptor A (GABA ) expression between the strains. For A it appears that extreme fearful behavioral responses in non- example, it has been found that BALB/c mice have signifi- human primates are associated with increased levels of stress cantly lower levels of benzodiazepine binding sites in the hormones such as cortisol and brain CRH, and also with amygdala compared to C57BL/6 mice (54). As described extreme right frontal brain activity versus left frontal brain below, alterations in the expression of GABAA receptors activity, a profile that has been found in humans suffering have been found to lead to increased anxiety-like behaviors from stress-related psychopathology (43). Taken together, 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.

The authors suggest that this increase reflects de- 100 order xalatan 2.5 ml line symptoms panic attack,635 (137 purchase xalatan 2.5 ml with visa treatment naive definition,138). The images are unusual because of the creased dopaminergic neurotransmission. Decreased synap- very high ratio of specific to nonspecific binding in the tic dopamine could then result in decreased occupancy of brain. Compared to images from labeled setoperone or al- the D2 receptors and D2 up-regulation, both factors could tanserin, in which approximately one-half of all of the brain lead to increased IBZM binding. In two other reports the activity is not bound to the receptor of interest, the IBZM uptake in the striatum was shown to decrease during [11C]WAY 100,635 PET images have less than 10% of the treatment with antidepressants (146,147), although de- activity in nonspecific binding and 90% specific activity. However, the striatal dopamine system may not assumed to be devoid of 5-HT1A receptors, is typically be the most critical in affective disorders. With the advent greater than 15, depending on the timing of the scan (com- of radioligands able to image extrastriatal D2 receptors (e. This [18F]fallypride) (148), investigation of dopaminergic func- very high 'target-to-background' allows the imaging and tion in limbic cortical regions will be possible. Early reports show 11 Conclusion that 5-HT1A receptor binding of [ C]WAY 100,635 in a variety of cortical regions and in the raphe is decreased in The last decade has produced numerous advances in our depressed patients compared to controls (139,140). Although the application served decreases are substantial, ranging from 20% to 40% to affective disorders has been limited to date, the data are in some regions. As 5-HT1A receptors are involved in wide- tantalizing. Findings have identified abnormalities in the spread modulation of function in limbic and paralimbic function of limbic cortical structures and the location of regions, these findings are of considerable importance. Fur- these structures overlap with those areas involved with gen- thermore, the 5-HT1A receptors are part of the autoregula- eration of emotion. With increasing sophistication of emo- tion of serotonergic innervation in the raphe, increasing the tional paradigms, a more precise picture of the role these significance of these findings. Serotoner- Work on imaging serotonin reuptake sites, the target of gic alterations are being further identified with existing tech- the most commonly used antidepressants, is ongoing. The niques and new radioligands will be introduced over the radioligand that has undergone the most study is next decade that will greatly expand our imaging capabili- [11C]McNeil 5652. Novel methods will be explored, leading to agents able tracer is high, and separating the receptor binding from to image aspects of gene expression, perhaps even with the nonspecific binding has been challenging (141,142). This tracer binds to other reuptake sites but has simpler kinetics and can be used in brain regions that have predominantly ACKNOWLEDGMENT serotonin reuptake binding. This property was exploited in a study by Malison and co-workers of unipolar, unmedicated Yvette I. Sheline was supported in part by MH01370 and depressed patients in which brainstem serotonin reuptake MH58444. Another area of interest is in the in vivo measure of serotonin synthesis. This has been achieved REFERENCES using -11C-methyl-tryptophan (144). MRI of the verted to - C-methyl-serotonin within neurons and then caudate nuclei in depression. Arch Gen Psychiatry 1992;49: accumulates, unable to be degraded by monoamine oxi- 553–557. The rate of accumulation is argued to be proportional 2. Quantitative Chapter 74: Imaging of Affective Disorders 1077 cerebral anatomy in depression: a controlled magnetic resonance impairment: a meta-analysis of the association, its pattern, and imaging study. Glial changes in the tal cortex abnormalities in mood disorders. Nature 1997;386: amygdala and entorhinal cortex in mood disorders. Structural neuroimaging and mood magnetic resonance imaging findings in geriatric depression. A mag- cerebral anatomy of the aging human brain: a cross-sectional netic resonance imaging study of putamen nuclei in major study using magnetic resonance imaging. Localization of white matter evidence for neuronal and glial prefrontal cell pathology in and other subcortical abnormalities. Absence of striatal volume differences be- ual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA tween healthy depressed subjects and matched comparisons. In vivo assess- tions in pre- and postsynaptic serotonin binding sites in the ment of pituitary volume with magnetic resonance imaging and ventrolateral prefrontal cortex of suicide victims. Brain Res systematic stereology: relationship to dexamethasone suppres- 1995;688:121–133. Hippocampal atrophy in imaging in major depression: focal changes in orbito-insular recurrent major depression.

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Increases in the current thresholds to predict violent buy xalatan 2.5 ml low cost symptoms dengue fever, pathologic aggression in humans purchase 2.5 ml xalatan medicinenetcom. In con- for aggression indicate antiaggressive effects, considered spe- trast to the more natural models (isolation-induced, resi- cific if simultaneously the drug does not affect thresholds dent-intruder, maternal aggression), this model is not sensi- for locomotion. Several drugs have been analyzed in this tive to certain intervening variables present in the other model, including benzodiazepines, neuroleptics, psycho- paradigms (anxiety, fear, sedation, and motor and sensory stimulants, alcohol, 5-HT -receptor agonists, serenics (5- disturbances) and directly reflects antiaggressive properties 1A HT1A/1B-receptor agonists) and selective serotonin reuptake of drugs. In addition, this model is not completely artificial inhibitors (56–59). For example, such animals do not attack rats on aggression and teeth-chattering thresholds at lower doses that previously have defeated them or females in estrus. The and enhanced the thresholds for both aggression and loco- predictive validity of this model seems to be somewhat less motion only at high doses, presumably reflecting the muscle than the other models; nonetheless, the model is useful in relaxant properties at these doses. Alcohol, up to a dose of determining how drugs bring about the antiaggressive effect. This sharply contrasts with the defensive rep- Although aggression is often considered a male-related phe- ertoire, which is characterized by submission, flight, and nomenon, females can be quite aggressive under certain con- similar reactive behaviors. Fighting, when it occurs in a de- ditions, such as in hypothalamically induced aggression in fensive animal, is merely a reaction to attack. Other defen- rats (54,55), aggression in nonestrus hamsters (58), and ma- sive behaviors, such as flight or submission, are apparently ternal aggression in several rodent species (59,60). The use intended to escape from or prevent further agonistic interac- of a female aggression paradigm to model human (female? Some of the drugs known to suppress offensive aggression has been quite uncommon, particularly for psy- behaviors have highly undesirable effects on defensive be- chopharmacologic purposes. The maternal aggression havior; for example, neuroleptics inhibit all activities includ- model seems to constitute such a model because it shows ing defensive and flight reactions. Maternal aggression is highly purposeful, providing protection to the Pain- or Shock-Induced Defensive offspring. The maternal aggression paradigm is based on Behavior the finding that a lactating female rat or mouse with pups Delivering electric shockto the hind paws of a pair of rats or will exhibit offensive behaviors toward a wide variety of mice evokes so-called foot shock– or pain-induced aggression intruders. This behavior is most pronounced during the first (66). Similar behavioral responses can be found when cer- part of the lactating period (62,63). Because the critical tain drugs (apomorphine, mescaline) are given to pairs of stimulus is clearly the proximity of some threatening object animals. However, the behavior of the lactating animals mutually exhibit typical upright defensive postures female toward an intruder is clearly self-initiated, proactive, and squealing and the behavior is clearly reactive; without and not necessarily reactive to any threat initiated by the switching on the current, no agonistic interactions will intruder. Although this paradigm was extensively used in the needs extensive planning, several psychoactive drugs have past to assess antiaggressive activity of drugs, a confounding been tested in it and have led to a model with a comparable factor in the model is that the behavior-releasing factor predictive validity as the male offensive paradigms in rats (pain) can be masked by analgesic properties of drugs. The psy- fact, together with the limited behavioral repertoire exhib- chopharmacology of maternal aggression has been mainly ited in this paradigm, limits its utility considerably. Specificity of the antidefense pines and alcohol showed, at low doses, proaggressive ef- effects is calculated as the ratio between these two ED50 fects, which faded at higher doses because of nonspecific values. A high ratio indicates good antidefense specificity; effects (sedation, ataxia, and muscle relaxation). D-Amphet- low values suggest strong interfering effects. Serenics (eltoprazine and related muscle-relaxing effects (26,67). Serenics (eltoprazine, flu- phenylpiperazines) have a highly selective effect in this para- prazine, and others) appear highly selective; ratios of more digm, reducing aggression without affecting other behav- than 20 (fluprazine) or, in the case of eltoprazine, not deter- iors, including pup care. The critical role of the 5-HT1B minable have been found. Eltoprazine did, up to a very high receptor in this effect was again demonstrated by additional dose, not inhibit this foot shock–induced behavior, thereby pharmacology showing that modulating other serotonergic illustrating its highly selective antioffense character. Defensive Behavior in Rats (Intruder Model) MODELS OF DEFENSIVE BEHAVIORS A more natural model of defensive behavior is the behavior Those forms of agonistic behavior in which elements of shown by an intruder in the resident-intruder or maternal initiative and approach prevail belong to the offensive reper- aggression situation. Defending animals in these paradigms Chapter 118: Animal Models of Aggression 1705 use special tactics to protect the more vulnerable parts of (71). There has been a great deal of dispute about the nature their bodies. In unconstrained conditions, animals on the of muricide in rats, resulting in various descriptions of the defense usually flee from the territory of the residential male behavior including, interspecies aggression (72), predatory or lactating female, but when this is impossible, as in labora- aggression (73), or simply predatory behavior (74). This tory conditions, they defend themselves by flight, crouch- model is clearly different from those described earlier, and ing, upright defensive postures, emission of ultrasounds, its human equivalent is questionable, although predatory and submissive postures. Generally, these behaviors aim at aggression has been described in relation to pathologic ag- protecting the back, the area where most wounds are in- gression in humans. Predatory attackclearly differs from flicted by attacking rats (68).

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