By P. Grimboll. Kansas City Art Institute.

Physiol Rev 1997; beta/A4 amyloid protein precursor order 10mg zetia with amex. J Neurochem 1995;65: ments by metal-catalyzed oxidation safe zetia 10mg. Neurotrophic and neu- macroglobulin and other proteinase inhibitors do not interfere rotoxic effects of amyloid beta protein: reversal by tachykinin with the secretion of amyloid precursor protein in mouse neuro- neuropeptides. Neuropathol Appl Neurobiol synthesis and secretion of normal and artificial mutants of mu- 1999;25:81–97. J Cell phorylates the calmodulin-binding regulatory regions of neu- Biol 1993;121:295–304. Ann NY Acad Sci 1992; vated protein (MAP) kinase transforms tau protein into an Alz- 674:118–128. Phosphorylation of tau coated vesicles purified from PC12 cells. J Biol Chem 1993;268: protein by casein kinase-1 converts it to an abnormal Alzheimer- 608–612. Phosphatase activity toward beta-amyloid precursor protein to lysosomes: alternative pro- abnormally phosphorylated tau: decrease in Alzheimer disease cessing into amyloid-bearing fragments. Beta-amyloid precursor protein cleavage by a mem- cause frontotemporal dementias. Role of genetics in test of genotype, status, 6075–6079. Segregation of and recycling as detected by labeled monoclonal antibody. J a missense mutation in the amyloid precursor protein gene with Cell Sci 1996;109:991–998. The genetic protein precursor to potentially amyloidogenic derivatives. Regulation and sor protein and the genesis of amyloid beta-peptide. Curr Opin Neurobiol 1994;4: Brain Res 1998;117:379–395. A mutation in the amyloid amyloid beta-protein precursor. Proc Natl Acad Sci USA 1986;83: of the beta-amyloid precursor protein gene. Neurobiol Aging 1995;16: and cerebral haemorrhage linked to a mutation at codon 692 365–371; discussion 371–380. A pathogenic muta- epitopes of paired helical filaments. Leu171Pro mutation in presenilin-1 gene in a Mexican family 93. Nilsberth C, Westlind-Danielsson A, Eckman CB, et al. Nat Neurosci 2001;4: presenilin-1 mutations with a novel phenotype. The Alzheimer family of diseases: many etiologies, one 114. Proc Natl Acad Sci USA 1997;94: of two missense mutations in the presenilin I gene in Japanese 2095–2097. A novel pathogenic beta protein from a mutant amyloid beta protein precursor. An increased percentage to deletion of exon 9 of presenilin 1. A further presenilin protein precursor (beta APP717) mutants. Proc Natl Acad Sci USA 1994;91: Nature 1995;376:775–778. A pedigree with a phorylation and oligomeric assembly of presenilin 1. Proc Natl novel presenilin 1 mutation at a residue that is not conserved Acad Sci USA 1997;94:5090–5094. The structure of the the Alzheimer disease-associated presenilin-1 generates an in presenilin 1 (S182) gene and identification of six novel muta- vivo substrate for protein kinase C. Proc Natl Acad Sci USA tions in early onset AD families. Endoproteolysis mutation (N141I) linked to familial Alzheimer disease (Volga of presenilin 1 and accumulation of processed derivatives in German families) increases the secretion of amyloid beta protein vivo. Effects of PS1 deficiency J Biol Chem 1997;272:24536–24541. The Notch pathway: democracy and dation and complex formation. J Biol Chem 1998;273: aristocracy in the selection of cell fate.

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Lower density of CB1 receptors is present Studies have revealed that activation of the subunits of G /i in discrete nuclei of other brain regions such as the hypo- Go proteins discount zetia 10mg, with subsequent inhibition of adenylate cyclase thalamus generic zetia 10 mg amex, brainstem, thalamus, and limbic forebrain, thus through both CB1 and CB2 receptors (47), blockade of volt- possibly accounting for THC activity on body temperature, age-activated calcium (Ca2 ) channels of the N- and P/Q- appetite, supraspinal mechanisms of pain perception, sen- type through CB1 receptors (48), and activation of inwardly sory perception, and mood or reward. CB1 receptors are rectifying potassium channels through CB1 receptors (49), associated with nerve fibers and axon terminals, but not may not be the sole intracellular signaling messages deliv- in the neuronal soma. This pattern is consistent with the ered by psychoactive cannabinoids. There is now evidence presynaptic inhibitory effects of cannabinoids on neuro- for the coupling of CB1, but not CB2 receptors, to Gs pro- transmitter release in the brain (see ref. CB1- teins, with consequent activation of adenylyl cyclase. It is expressing cells in mouse forebrain can be divided into dis- not clear yet whether this effect may explain the biphasic tinct neuronal subpopulations. Most of the cells that highly nature of cannabinoid effects on behavior in several tests. In the hippocampus, amygdala, and entorhinal cortex THC and synthetic and endogenous cannabinoids can area, CB1 mRNA is present at low but significant levels either stimulate (50) or inhibit (51) NO formation. The in many non-GABAergic cells that can be considered as former effect results in inhibition of dopamine release from projecting principal neurons. These data are in good agree- invertebrate ganglia, whereas the inhibition of NO release ment with the observation that cannabinoids act on princi- in granule cerebellar cells seems to result from inhibition pal glutamatergic circuits as well as modulate local GABAer- of voltage-activated Ca2 channels. In any case, modulation gic inhibitory circuits by inhibiting glutamate and GABA of NO levels may result in changes in cyclic guanosine Chapter 106: Marijuana 1523 monophosphate intracellular concentrations. Finally, pro- sients in HL60 cells through these receptors. Interestingly, tein phosphorylation catalyzed by mitogen-activated pro- in this study, AEA was shown to be a very weak and partial tein kinase is coupled to both CB1- and CB2-receptor stimu- agonist at CB2 receptors. This intracellular effect, together with agonist at CB2 receptors, AEA, and much more so its meta- inhibition of the cyclic adenosine monophosphate bolically stable analogues (R)-methanandamide and 2′-flu- (cAMP)–dependent protein kinase A, is at the basis of can- oro-2-methyl-arachidonoyl-ethanolamide, act as relatively nabinoid action on the expression of several genes such as potent (Ki between 12 and 100 nM) and selective CB1- krox-24 in HL60 cells (52) or the prolactin receptor and receptor agonists, and thus can be considered useful phar- the high-affinity receptors trk for the nerve growth factor in macologic tools for studies on the bioactivity of endocan- human breast cancer cells (53). Likewise, bly in part because of the rapid metabolism of this com- CB1-induced activation of focal adhesion kinase in hippo- pound both in vitro and in vivo (59), and because AEA is campal slices, an effect suggested to lead to modulation by a partial agonist in some functional assays of CB activity 1 cannabinoids of synaptic plasticity and learning, results (60). In the brain, AEA was shown to exert inhibitory ac- from inhibition of adenylate cyclase and protein kinase A. These ef- Endogenous Ligands (Endocannabinoids) fects probably result from the capability of AEA to induce, by activation of CB1 receptors, modulation of neurotrans- Since the mid-1990s, several fatty acid derivatives have been mitter (e. This neuromodula- substances, however, can displace high-affinity cannabinoid tory action may also underlie AEA regulation of hormone ligands from selective binding sites in membrane prepara- release at the level of the hypothalamus-pituitary-adrenal tions containing the CB1 or the CB2 receptor. Anandamide axis, as well as the antinociceptive effects of the compound (arachidonoylethanolamide, AEA), the amide of arachi- through both spinal and supraspinal mechanisms (63). The other prominent endoge- lated through the regulation of either their biosynthesis or nous ligand is a glycerol ester, 2-arachidonoyl glycerol inactivation. It is commonly accepted that the AEA and 2- (2-AG) (55). These compounds share the ability to bind to AG are not stored as such in cells, but rather are synthesized and to activate CB1 and (particularly in the case of 2-AG) 2 and are directly released by cells 'on demand,' after Ca CB2 receptors. Therefore, they induce a series of pharmaco- influx into the cell (such as that occurring in neurons on logic effects in vitro and in vivo that are, to some extent, depolarization or in mast cells after IgE-mediated activa- similar to those exerted by THC. Other fatty acid deriva- tion) and the hydrolysis of phospholipid precursors (40). The molecular mode of action nolamines (NAPEs) (64). This reaction is catalyzed by a of these latter compounds is still a subject for investigation. Several mechanisms for 1 tionship can be best appreciated with a successful conforma- the inactivation of endocannabinoids have been identified tional model (57), in which AEA may assume a low-energy in neuronal and blood cells. A membrane-bound intracellu- conformation resulting in the superimposition of its n-pen- lar hydrolase catalyzes AEA hydrolysis after its diffusion into tyl chain, carbonyl amide group and ethanolamine hydroxyl neuronal cells and leukocytes (64). A mechanism for the group, respectively, with the n-pentyl chain, the phenolic facilitated diffusion of AEA into cells according to its con- hydroxyl group and the C-9 hydroxyl group in 9-nor-9 - centration gradient across the plasma membrane has been OH-hexahydrocannabinol, a potent THC analogue. Struc- partially characterized as a saturable, temperature-sensitive, ture-activity relationship studies for the interaction with selective and sodium-independent 'carrier' (64). This 'car- CB2 receptors have not been performed yet, the sole excep- rier,' probably a protein, may be used for both the reuptake tion being the article by Sugiura et al. The major enzyme moieties necessary to 2-AG analogues to induce Ca2 tran- responsible for AEA hydrolysis is the fatty acid amide hy- 1524 Neuropsychopharmacology: The Fifth Generation of Progress drolase (FAAH), cloned so far in four different mammalian analgesia while leading to the release of AEA in microdialy- species (65). Moreover, the Because the biosynthetic precursors for AEA and 2-AG, injection of formalin into the paw induced a nociceptive by being products of membrane phospholipid remodeling, response concomitantly to the release of AEA from the peri- are likely to occur in most animal tissues, the two endocan- aqueductal gray and thereby established an correlation be- nabinoids are probably to be found, at least in minute tween supraspinal nociception and endocannabinoid re- amounts, as ubiquitous metabolites. In fact, an earlier investigation had suggested that an compounds to work as endogenous agonists of CB1 and endocannabinoid tone may down-modulate pain percep- CB2 receptors, their tissue concentrations need to be in- tion through CB1 receptors in another region of the brain- creased up to at least 50 to 100 nM after cell stimulation stem, the rostral ventromedial medulla, through the same (e. Furthermore, the inactivation of endocan- shown that blockade of the action or expression of spinal nabinoids may be subject to regulation. In agreement with CB receptors by SR141716A or a CB -receptor antisense 1 1 possible regulation of endocannabinoid levels under physio- oligonucleotide, respectively, leads to hyperalgesia (76), a logic and pathologic conditions, the amounts of AEA or 2- finding thus suggesting the existence of an endocannabinoid AG have been found to vary during brain development, to tone down-modulating nociceptive response also at the be higher in some of the brain regions with the highest spinal level.

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CRH produces signs and support the hypothesis that TCAs are either ineffective or symptoms of depressive and anxiety disorders by activation much less effective in this age group than in adulthood zetia 10mg on-line. These findings provide Furthermore cheap 10 mg zetia with mastercard, TCAs are particularly toxic in deliberate or a rationale for attempts to develop medications that antago- accidental overdose in youth, and they are all off patent; nize the CRH1 receptor. Zobel and colleagues (144), using therefore, more studies of TCAs in this population are un- R121919 (an agent that binds to CRH1 receptors) in an likely. CRH1 receptor blockade did not to placebo (155,156) and they appear equally efficacious in impair corticotropin and cortisol secreting activity either at prepubertal children as in adolescents and in both sexes baseline or after an exogenous CRH challenge. Encouraged by regulatory changes, randomized, pla- These early reports are tantalizing. The field awaits more cebo-controlled trials in youth are planned or underway for definitive, placebo-controlled clinical trials for both CRH essentially all antidepressants now on patent. Whether these agents will have One of us has argued, post hoc, that because the TCAs predictable, substantial, and prolonged antidepressant or as a group are all relatively noradrenergic in youth because anxiolytic (e. In theory, if they modify stress responses, such noradrenergic antidepressants as a class will prove less useful agents may be important in the treatment of residual symp- in youth, whereas serotonergic antidepressants will show toms or symptomatic breakthroughs that occur with cur- efficacy throughout the lifespan. Alternatively, they may prevent the able RCTs on newer agents other than SSRIs in youth to onset of a depressive episode following a stress in vulnerable further address this question (157). Although available and ongoing work in antidepressant Combinations of standard medications, especially the use pharmacology in youth with MDD provides guidance for of atypical antipsychotic agents, alone or combined with the initial treatment step for depression, the field is only antidepressants, have begun to be a focus of research for now considering the arguably more important studies of treatment-resistant depression (145,146). The rationale for chronic maintenance, combination treatment, treatment of the use of olanzapine combined with fluoxetine, for exam- refractory depression, and the other questions that arise in ple, is provided by evidence of increases in norepinephrine this recurrent disorder. In a recently completed, 8-week, double- blind trial in 28 patients with treatment-resistant depres- sion, large reductions in MADRS scores were obtained with 'ALTERNATIVE' THERAPIES the combination, as compared to either agent alone (146). These extracts contain at least 10 biologically active substances. One study has suggested that hyperforin may be the critical active constitu- ANTIDEPRESSIVE TREATMENTS IN ent (158). Extracts of hypericum inhibit reuptake of seroto- CHILDREN AND ADOLESCENTS nin, norepinephrine, and dopamine and lead to down-regu- lation of -adrenoceptors and serotonin (5-HT2) receptors The psychotherapeutic approaches of cognitive behavioral (159). However, limiting the studies to date is the lack of therapy (CBT) and IPT appear to have specific efficacy in a standardized concentration of the active ingredient(s) in adolescent depression (147–152), whereas psychotherapeu- the preparation of hypericum extract. As reviewed elsewhere (154), RCTs of TCAs versus less in all but the Philipp study that used 100 mg of imipra- placebo have been uniformly negative in both children and mine for 8 weeks). Many of these negative studies were relatively and the SSRI fluoxetine also found no statistically signifi- small. However, when considered in aggregate, the data best cant difference between treatments (mean decrease in Chapter 75: Current and Emerging Therapeutics for Depression 1089 HAM-D score 10. In a recent double-masked randomized study (165) of In aggregate, these data seem to point toward efficacy 201 outpatients with major depression and a baseline 17- and perhaps very rapid onset of SAMe in the treatment of item HAM-D score 20 treated for 8 weeks with either adult major depressive disorder. However, there was no significant differ- almost all comparison studies were conduct for far too short ence seen between St. The roles of either the continuous outcome measures, including the HAM-D, SAMe or St. The very low rate of response both to active may be a useful focus of study. Acupuncture Thus, although the randomized clinical studies using pla- cebo suggest that hypericum has some antidepressant effect As reviewed in Ernst and colleagues (171), several case series in humans (and has effects in animal models for depression), and open clinical trials suggest possible efficacy of acupunc- the data are simply inadequate to say how well St. The NIMH and National Institutes of Health Office ture to amitriptyline. One study (172) compared 5 weeks on Alternative Medicine is currently funding a study of of amitriptyline (average daily dose 142 mg) to electro-acu- hypericum perforatum versus SSRI or placebo, which may puncture in a total of 47 subjects and found no significant further elucidate the efficacy of this compound. A larger replication found no significant difference in outcome between amitriptyline and electro-acupuncture in a 6-week RCT in a total of 241 S-adenosyl-L-methionine depressed inpatient subjects (173). As is well understood, lack of statistically significant difference of a putative treat- S-adenosyl-L-methionine (SAMe) has been tested as a po- ment from a 'known effective' treatment is not strong evi- tential antidepressant over the past 25 years. It is the primary dence for the efficacy of a treatment. In addition, the dura- methyl donor in the CNS for methyl acceptor molecules tion of treatment was relatively short, which would including catecholamines and phospholipids. A 1994 underestimate the maximal amitriptyline effect in these metaanalysis (167) examined the literature through 1992, studies. Although those authors be specific to the treatment of depression), placebo acu- found the aggregate data to show statistically significant puncture (acupuncture at nonspecific locations) or no acu- superiority of SAMe to placebo and equivalence of SAMe puncture. Both the specific and control acupuncture treat- to TCAs, all but two of the comparisons with placebo and ments showed statistical superiority to the no acupuncture two of the comparisons with TCAs were 21 days or less in group on several of the measures, although the differences duration. Equivalence to TCA for such a short interval (be- were not large. There was no difference on any measure fore most of the TCAs effects have been realized) is uncon- between the specific and control acupuncture treatments in vincing.

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