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Chapter 71: Bipolar Disorders: Review of Molecular Genetic Linkage Studies 1035 50 human genes cheap kamagra soft 100mg on-line. It is likely that imprinting will explain CTG repeats on 17q and 18q21 (116) 100mg kamagra soft mastercard. The hypothesis that some of the complex inheritance of BPD buy generic kamagra soft 100 mg line. ANTICIPATION AND TRIPLET REPEATS IMPLICATIONS OF THE HUMAN GENOME Anticipation is the term used to define an observation that PROJECT a familial disorder occurs with earlier age at onset and/or increasing severity among younger generations, compared The Human Genome Project is nearing completion of one to older generations. Anticipation occurs in several neurode- of its primary goals, the sequence of the human genome. Once this goal is achieved, the most important task anticipation in these disorders involves unstable intragenic will be the definition of function for each expressed se- trinucleotide repeats, which expand in subsequent genera- quence (functional genomics). Implied (but not included) tions, giving rise to increasing levels of gene disruption and in this goal is the function of each protein (functional pro- thus to earlier age at onset and increasingly severe phenotype teomics), involving interactions between proteins. Individuals with earlier age-at-onset BPD disor- and RUP disorder will be facilitated remarkably by the com- der may have reduced capacity to reproduce, so parents with pletion of these Human Genome Project milestones noted such early-onset disorders may be underrepresented in the above. At present our knowledge base regarding central ner- general population. Individuals with familial BPD disorder vous system (CNS) function and the biochemical etiology may come to treatment earlier than those with sporadic of BPD and RUP disorder is so poor that too many brain- disease, such that less severe mood disorder episodes are expressed genes may be considered candidates. This limita- detected medically, and an earlier age at onset is defined. Because 20 mood disturbance in terms of 'diagnosable syndromes. These discovering a single disease gene within such a region, impli- linkage studies select for earlier age-at-onset cases, because cated by linkage, is the proverbial equivalent of finding a preference is given to densely affected kindreds. Among needle in a haystack, with currently available DNA technol- broader cultural factors possibly underlying the evidence of ogies. However, once all expressed sequences are known, anticipation, if stigma concerning mood disorders is less and their functions are understood, it is possible to focus on among younger affected persons (compared to older indi- the few best candidates. This reduces an intractable problem viduals), then younger cohorts might describe their experi- (from a DNA technology perspective) to a manageable size. These potential confounding factors make Genome Project goals are approached. The hypothesis that anticipation in BPD disorder reflects causative expanding trinucleotide CTG repeat sequences has generated genomic searches for such sequences SUMMARY (110–113), using the repeat expansion detection method (114). These three groups have noted increased lengths of Despite the extensive data (from twin, family, and adoption CTG repeats in BPD disorders, especially among those with studies) for genetic factors in BPD, gene identification familial disease. However, not all studies have reported this through linkage studies has been elusive. There are multiple difference (115), and no report shows transmission of an confirmed BPD linkage regions across the human genome, expanding repeat within BPD families, the definitive evi- but the effect sizes are uniformly small at each locus. Furthermore, greater than 90% of the expanded ing genes from these small effect size regions is a challenge CTG repeats detected by the method of Schalling et al. Part of the complexity (114) are from two apparently nonpathogenic unstable of BPD genetics may be due to imprinting, mitochondrial 1036 Neuropsychopharmacology: The Fifth Generation of Progress inheritance, and trinucleotide repeat expansion. A Danish twin study of mendelian influences require additional research. Am J Psychiatry 1974;131: ACKNOWLEDGMENTS 1234–1239. Adoption study supporting genetic transmission in manic-depressive illness. Nature 1977; This paper was prepared with the support of National Insti- 368(5618):327–329. Psychiatric disorders Alliance for Research on Schizophrenia and Depression Dis- in the biological and adoptive families of adopted individuals tinguished Investigator Award. Evidence for genetic inheritance of primary affec- tive disorder in adoptees. A family study of tion study of depressive disorders and substance abuse. Arch schizoaffective, bipolar I, bipolar II, unipolar, and normal con- Gen Psychiatry 1983;40:943–950. Psychiatric disor- specifying genetic parameters in LOD score analysis. Biometrics ders in the relatives of probands with affective disorder. Schizoaffective illness, schizo- of linkage analysis. The Iowa 500: affective Am J Hum Genet 1996;58:1347–1363. Genetic dissection of complex traits: chiatry 1982;139:209–212. Arch Gen Psychiatry search for human non-insulin-dependent (type 2) diabetes genes 1995;52(5):367–373. A family interview study of male manic- Genet 1996;13(2):161–166. A genetic study of bipolar affective generation screen of the human genome for susceptibility to disorder. Bipolar manic depressive search for human type 1 diabetes susceptibility genes. Nature psychoses: results of a genetic investigation. Morbidity risks in subtypes of unipolar risk factor for Alzheimer disease. Am J Hum Genet 1994;54: depressive illness: differences between early and late onset forms. Recurrent and nonrecurrent interval mapping and exclusion for complex genetic traits. Arch Gen Psychiatry 1988;45: 82nd Annual Meeting of the American Psychopathological As- 328–336. Washington, DC: American Psychiatric Press, 1994: 16. A population-based markers and manic depressive illness: evidence for a susceptibil- twin study of major depression in women: the impact of varying ity gene. A hospital-based twin disorder to chromosome 18 with a parent-of-origin effect. Am register of the heritability of DSM-IV unipolar depression. Evaluation of linkage Chapter 71: Bipolar Disorders: Review of Molecular Genetic Linkage Studies 1037 of bipolar affective disorder to chromosome 18 in a sample of 60. Lithium responsive bipo- at high risk for bipolar affective disorder among the Old Order lar disorder, unilineality and chromosome 18: a linkage study. Support for a chromo- and chromosome 18 allele sharing in unilineal bipolar illness some 18p locus conferring susceptibility to functional psychoses pedigrees. Parental transmission and D18S37 allele sharing Genet 1994;8:291–296. Further evidence for bility locus for bipolar disorder on 21q. Am J Hum Genet 1996; a susceptibility locus on chromosome 10p14-p11 in 72 families 58:1279–1285. Further tests for linkage Med Genet 1999;81:302–307. Evaluation of a suscep- locus on chromosome 11p15 in a new series of multiplex British tibility gene for schizophrenia on chromosome 6p by multipoint affective disorder pedigrees. Am J Psychiatry 1996;153: affected sib-pair linkage analysis. A potential vulner- tion-based statistical analyses for bipolar affective disorder locus ability locus for schizophrenia on chromosome 6p22-24: evi- on chromosome 21q22. An international pedigree derived from a homogeneous population in Quebec two-stage genome-wide search for schizophrenia susceptibility points to a locus of major effect on chromosome 12q23-q24. A genome survey pean-American schizophrenia kindreds: results of the NIMH indicates a susceptibility locus for bipolar disorder on chromo- Genetics Initiative and Millennium consortium. Detera-Wadleigh SD, Hsieh W-T, Berrettini WH, et al.

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Levels of CSF 5-HIAA are lower is that most of the depressive subjects who have been studied in depressed patients with a history of serious suicidal behav- died as a result of suicide purchase kamagra soft 100mg line, and the relationship between the ior cheap 100 mg kamagra soft fast delivery, as compared to depressed patients with no history of biological abnormalities found in the central noradrenergic suicide attempts buy kamagra soft 100mg cheap. CSF 5-HIAA is not distinguished by more severe If one accepts that biological abnormalities in the nora- depression, but by a history of serious suicide attempts (55). Again, it is presently nec- In depressed patients who had recent therapeutic responses essary to look to laboratory animal studies to examine this to antidepressant medications, tryptophan depletion causes issue. Repeated treatment of rats with antidepressants from a transient depressive relapse (35). Rapid tryptophan deple- many different pharmacologic classes (including 5HT up- tion of many, but not all, patients with a history of depres- take inhibitors), but not with non-antidepressant drugs, sion and that are antidepressant drug-free causes a depressive down-regulates LC tyrosine hydroxylase (114). In symptomatic, medication-free patients sant drug treatment blocks stress-induced elevation of tyro- with depression, tryptophan depletion causes no significant sine hydroxylase mRNA in the rat LC (154). Repeated behavioral effects (36), perhaps because of a floor effect (36). These findings demonstrate but not always, associated with a serotonergic deficit. Returning to the suggestion that LC activity may be been reported. Measurement of both 5HT1A different pharmacologic classes (including 5HT uptake in- and 5HT2A receptors in the prefrontal cortex from suicide hibitors) reduces LC activity (58,68). Hence, animal data victims has yielded no clear conclusions. Most of the studies strongly support the contention that drugs produce antide- cited in a recent review of these data by Stockmeier and pressant effects, at least in part, by reducing demand for NE, colleagues (165) utilized tissues primarily from victims of that is, reducing biochemical measures of demand (reduced suicide. Because there is an association of serotonergic ab- biosynthetic enzyme for NE) and reducing LC activity. Sig- mal levels of noradrenergic proteins in the LC of human nificant increases in 5HT2A receptor binding and a decrease major depressives, 3) the ability of antidepressant medica- in 5-HIAA in major depressives dying of causes other than tion to produce effects that would be expected to reverse suicide have been reported (47,103). Two major nuclei in the brain, SEROTONERGIC CIRCUITRY AND from which the majority of brain serotonergic innervation DEPRESSION originates, are the dorsal raphe and median raphe nuclei. These nuclei provide an extensive innervation of cortical The biological basis for the indoleamine hypothesis was sim- and subcortical target areas. The dorsal and median raphe ilar to that for the catecholamine hypothesis (178). That is, nuclei give rise to separate axonal pathways to different brain reserpine depletes not only catecholamines, but also 5HT. For example, the septum and hippocampus are in- Since that time, several (but not all) studies have found nervated predominantly by the median raphe nuclei. In con- reduced levels of CSF 5-hydroxyindole acetic acid (5-HIAA) trast, the striatum and substantia nigra are innervated by in depressed patients (101,179); however, the degree of re- the dorsal raphe nuclei. Serotonergic terminals densely in- duction of CSF 5-HIAA does not correlate with severity of nervate various components of the limbic system. Oddly, many antidepressant medications, par- spread innervation of the brain by serotonergic neurons is ticularly 5HT reuptake inhibitors and monoamine oxidase the anatomic basis for the influence of 5HT on many diverse inhibitors (MAOIs), reduce CSF 5-HIAA, possibly because brain functions. Using single photon emission com- convulsive shock to rats does not appear to desensitize so- puted tomography (SPECT), Malison and associates (97) matodendritic autoreceptors, although these treatments reported a decrease in 5HT transporter availability in the enhance the responsiveness of postsynaptic 5HT receptors brainstem of living subjects with major depression. Hence, the mechanism by which different antide- of issues related to spatial resolution, it is difficult to con- pressant drugs regulate serotonergic activity appears to dif- clude from this study that the reduction in 5HT transporter fer, but the net effect of enhancing serotonergic transmission occurred in raphe nuclei and/or other brainstem nuclei is similar. These preclinical findings are consistent with the where the 5HT transporter occurs (e. Little and co-workers (90) found no significant in depressive disorders that is normalized or corrected by change in mRNA for the 5HT transporter in the dorsal antidepressant drug administration. Consistent with these findings, Bligh-Glover and colleagues (25) found no significant dif- DOPAMINERGIC CIRCUITRY AND ferences between depressed suicide victims and normal con- DEPRESSION trol subjects in [3H]paroxetine binding to the 5HT trans- porter in the entire dorsal raphe or in its constituent Since the discovery that tricyclic antidepressant drugs can subnuclei, as determined using postmortem tissues from block DA reuptake in vitro (66), and that elevation of the psychiatrically characterized subjects. An increase in radioli- functional activity of DA has antidepressant efficacy (142, gand binding to 5HT1A autoreceptors in dorsal raphe nuclei 143), there has been interest in the potential role of DA in from depressed suicide victims has been observed (166). The contribution of DA apparent contrast, a decrease in the binding potential to to emotion-laden behaviors such as reward seeking, motiva- 5HT1A receptors in the midbrain raphe nuclei has been tion, and environmental responsiveness also raises specula- observed using positron emission tomography (PET) in pa- tion that DA plays a role in the pathobiology of depression tients with familial mood disorder (38). In fact, clinical, pharmacologic, and laboratory provide evidence of morphologic abnormalities of brain- animal evidence suggests that dopaminergic neurotransmis- stem serotonergic nuclei. Underwood and associates (173) sion is decreased in depression. Lower concentrations of have demonstrated elevated numbers and densities of 5HT homovanillic acid (HVA), a DA metabolite, have been ob- neurons in the dorsal raphe of suicide victims, most of served in CSF of patients with depression, and depression- whom had major depression. In addition, Becker and col- inducing effects of DA-depleting agents or DA antagonists leagues (18) have demonstrated significantly low echogeni- have been reported (143,144,189). In contrast, agents that city of the dorsal raphe nucleus in patients with major enhance DA transmission, at least in part, such as buprop- depression using a novel transcranial ultrasound technique. Given that DA is intimately involved in pathologic involvement of brainstem serotonergic nuclei in motivational process and affect (73,167), these findings sug- depression, but the study by Underwood and associates gest that a deficiency of mesolimbic and/or mesocortical ruled out a loss of serotonergic neurons in depressed sui- DA is a leading candidate for the etiology of core symptoms cides, suggesting that the postulated hypofunction of the of depression, such as difficulty in the experience of pleasure serotonergic system is not owing to fewer serotonergic neu- (anhedonia), social isolation, loss of motivation (lack of in- rons, but dysfunction of serotonergic neurons. As is the case terest), and psychomotor retardation (190). In fact, repeated treatment of rats dysfunction or activation of mesolimbic and/or mesocorti- with antidepressant drugs results in a net enhancement of cal DA systems are implicated in psychiatric disorders, in- serotonergic transmission (24). This effect is regardless of cluding depression, schizophrenia, and psychostimulant the primary pharmacologic site of action of the drug and drug abuse disorders. However, some overlap in the pathol- includes selective 5HT transporter inhibitors, MAOIs, tri- ogy of PD and psychiatric disorders apparently occurs be- cyclic antidepressants, and electroconvulsive shock. Selec- cause cell loss in the VTA (in addition to substantia nigra) tive 5HT transporter inhibitors and MAOIs enhance sero- has been observed in patients with PD who have complica- tonergic transmission by desensitizing the somatodendritic tions of co-morbid mood and cognitive disorders (171). Chronic administra- have delineated reciprocal pathways linking various limbic Chapter 73: Neurocircuitry of Mood Disorders 1055 and cortical regions with dopaminergic brainstem nuclei. A lower density of D1 receptors induced behavioral responses (75). This circuit includes the nucleus by chronic antidepressant medication might contribute to accumbens, amygdala, prefrontal cortex, mediodorsal thala- enhancement of D2 receptor functions as a result of a reduc- mus, ventral pallidum, and midbrain neurons located in the tion in the inhibitory interactions between these two recep- VTA. Of brain limbic structures, the nucleus accumbens tors at the level of the subunit of G proteins (182). Following expo- lished role in motivation and affect (167,75). Neurons in sure to uncontrollable foot shock, an animal model of the nucleus accumbens receive a highly compressed input depression, rats display a pronounced reduction of respond- from the amygdala, hippocampus, cingulate gyrus, and pre- ing for electrical brain stimulation of the nucleus accum- frontal cortex (68,194). This response is attenuated by repeated treatment with neurons in the nucleus accumbens are DA-containing fibers the antidepressant drug desipramine (193). Rats exposed to from the VTA (68), suggesting that the nucleus accumbens chronic mild stress, another animal model of depression, may integrate information coming from the prefrontal cor- experience decreased responsiveness to rewards (anhedonia), tex and limbic regions with those originating from the VTA. These behavioral Besides projecting to the nucleus accumbens, DA neurons changes are accompanied by lower D2/3 receptor binding ascending from the VTA project to other limbic structures, in the limbic forebrain that is reversed by 5 weeks of imipra- including discrete regions of amygdala, to cortical areas, and mine treatment (127). Overall, preclinical findings imply to the septum (116). Prefrontal, orbitofrontal, and cingulate that a putatively important pharmacologic effect of antide- cortices receive robust innervation from the VTA. Interest- pressant treatment is the augmentation of mesolimbic DA ingly, most of the areas receiving DA projections from the activity. A few recent studies have measured the DA receptors in If DA neurotransmission were disrupted in depression, depressed patients in vivo using brain imaging techniques. Numer- in the striatum in depression, possibly reflecting reduced ous studies demonstrate that antidepressant drugs enhance DA function and a consequential up-regulation of these mesolimbic DA activity. On the other hand, Ebert and associates, antidepressant drugs (tricyclics, mianserin, or citalopram) 1996 (43) found striatal D2 receptor binding unchanged in enhances DA agonist-induced locomotor hyperactivity, an major depression. It is noteworthy that stereotypy (a behavioral ef- INTERACTIONS BETWEEN THE fect reflecting the activity of nigrostriatal system) induced MONOAMINE NUCLEI AND MONOAMINES by D-amphetamine or apomorphine, is not increased by AND OTHER NEUROTRANSMITTERS repeated treatment with antidepressant drugs (156); there- fore, it has been assumed that the mesolimbic DA system Abnormalities of the biochemistry of one or more mono- mediates the increased behavioral responses to DA agonists amine systems may cause depressive disorders. Consistent with this disrupted monoamine biochemistry may be secondary to effect, antidepressant drug treatment increases the affinity other root biological, environmental, and/or psychological of D2 receptors for their agonist in the limbic forebrain, causes. A multitude of experimental approaches will be re- but not in the striatum (78) and chronic treatment with quired to determine the core cause(s) of depressive disorders, antidepressant drugs results in postsynaptic DA receptor even as considerable evidence of monoamine dysfunction supersensitivity in the nucleus accumbens (40). Nevertheless, it is interesting to toradiography studies confirm these findings by showing consider the relationship of the monoamines with other that when [3H]raclopride, an antagonist at D receptors, neurotransmitters that modulate monoaminergic chemistry.

A detailed handbook of HD treat- of worthlessness or guilt kamagra soft 100 mg with amex, self-blame generic 100mg kamagra soft with visa, changes in sleep and ment options was prepared by Rosenblatt and colleagues appetite buy kamagra soft 100mg with mastercard, anxiety, anhedonia, loss of energy, hopelessness, (6). Delusions and hallucinations, when pres- Treatment of Movement Abnormalities ent, tend to be mood congruent: delusions of poverty, ill- ness, or guilt; auditory hallucinations of derogatory or Chorea may be a disabling symptom, leading to bruises, threatening voices. The diagnosis of major depression may fractures, or falls and impairing the ability of patients to Chapter 125: Huntington Disease 1819 feed themselves. Other patients find the chorea of major Depressed patients should always be questioned about cosmetic concern. Treatment with high-potency neurolep- thoughts of suicide. When suicide is a concern, the patient tics, such as haloperidol and fluphenazine, may be indicated should receive as few pills as possible, especially if they are in such cases, but with important caveats. Furthermore, neuroleptics increase morbidity by depressed patients with hallucinations or delusions. Cloza- making patients more rigid, sedated, and apathetic. Doses fore not worsening aspects of the voluntary movement dis- higher than 10 mg per day of haloperidol yield little or no turbance. Electroconvulsive therapy is indicated for benefit over lower doses. If patients experience unacceptable depressed patients who are refractory to treatment with rigidity, akathisia or dystonic reactions to high-potency neu- medication, for patients with delusions, for those who are roleptics, lower-potency agents such as thioridazine may be not eating or drinking because of their depression, or for better tolerated. However, use of lower-potency neurolep- those who are at high risk of suicide. For patients with tics increases the risk of sedation, anticholinergic side effects, bipolar disorder, carbamazepine, divalproex sodium, or lith- and postural hypotension. Reserpine is a known cause of drug-induced depression, counterproductive, or therapeutic blood levels have been and the affective state of patients receiving this agent should reached. The benzodiazepine clonazepam In treating irritability, it is important to attempt to iden- may also be useful in the treatment of chorea, and it may be tify and to minimize precipitants such as hunger, pain, ina- of benefit in the later stages of the disease, when neuroleptic bility to communicate, frustration with failing capabilities, medication often has little effect. We have had success using selective Treatment of Cognitive Abnormalities serotonin reuptake inhibitors (7) and divalproex. Sexual dis- There is no known effective pharmacologic treatment for orders in HD, particularly aggressive hypersexuality, can be the dementia of HD. Cholinergic agents have not been sys- treated with antiandrogenic medications. Obsessive-com- tematically assessed in HD, but the rationale for using these pulsive disorder in HD can be treated with standard antiob- medications is less compelling than in Alzheimer disease, sessional agents, such as selective serotonin reuptake inhibi- because cholinergic neurons are relatively spared in HD. Patients can be instructed to jot down notes and reminders and to sequence tasks so they can concentrate on one at a time. Complex cognitive tasks should be minimized, and, DIFFERENTIAL DIAGNOSIS as the disease progresses, questions should be framed in a choice format with the provision of frequent cues to assist The clinical features of HD are often characteristic, and the recall. The diagnosis is less clear in patients with unchar- Treatment of Psychiatric Disorders acteristic presentations or a lack of family history (1,8). For Major depression in HD responds to the same treatments instance, patients may present with very little chorea or with used in idiopathic depression. In general, depression in HD movements that are predominantly athetoid, dystonic, or is underdiagnosed and undertreated, perhaps because of the even ticlike. All the affected members of a pedigree may propensity of clinicians to see it as an understandable reac- manifest atypical features of the disorder, such as prominent tion to having the disease. Although no controlled studies brainstem involvement, a finding contributing to diagnostic exist, our experience is that both tricyclic antidepressants confusion. Occasional patients (particularly with late onset) and selective serotonin reuptake inhibitors are effective. As may have only subtle movement abnormality and relatively with any neuropsychiatric disorder, patients should be little cognitive disorder (1,8). Fortunately, with the avail- started on low doses that are slowly increased while the ability of the HD gene test, it is now possible to establish patient is closely monitored for adverse effects, particularly the diagnosis of HD definitively even in patients with no delirium. It is important to remain with a medication for family history or an atypical presentation. Most patients a full therapeutic trial at adequate doses and blood levels. On a population basis, there is a clear distinction between HD is now recognized as part of a family of related neu- expanded and normal length repeats in huntingtin. Repeats rodegenerative disorders, all caused by expansions of CAG with fewer than 29 triplets are within the normal range. The diseases share certain The rare repeats with 29 to 35 triplets are considered of clinical features, especially ataxia and dementia, and can be intermediate length, prone to expansion but not in them- confused with each other. Among these diseases, Ma- selves of sufficient length to produce a phenotype. Various other diseases may also present with HD- HD was considered 100% penetrant. However, it is now like symptoms, including Wilson disease, Creutzfeldt–Ja- clear that penetrance (currently defined as the presence of kob disease, forms of ceroid neuronal lipofuscinoses, chorea signs or symptoms of HD by the age of 65 years) is less than with red blood cell acanthocytosis, hereditary nonprogres- 100% in persons carrying an allele with 36 to 40 triplets. For sive chorea, paroxysmal choreoathetosis, mitochondrial dis- instance, four of seven persons who were more than 70 years orders, corticobasal degeneration, basal ganglia calcification, old and who had a 36 triplet allele had no signs or symptoms forms of hereditary dystonia, Sydenham chorea, vitamin E of HD. One person with a 39 triplet allele died at the age deficiency, and cerebral vascular disease (10). Because alleles with 36 to 40 triplets are quite uncommon, the frequency of nonpenetrance is difficult to GENETIC ETIOLOGY estimate reliably. However, for repeats of 36 or 37 triplets, it may be on the order of 50%. Discoveryof the HD Mutation The discovery of the HD mutation revolutionized ge- HD was the first disease mapped (to chromosome 4p) using netic counseling of presymptomatic persons at risk of HD. The techniques of linkage analysis were used age analysis, a complex procedure requiring the cooperation to demonstrate that HD exhibited almost complete genetic of several family members. HD emerged as a model for dominance (13) and locus homogeneity (14). Many of the presymptomatic genetic testing, and most testing has been techniques of positional cloning, including marker develop- carried out under careful protocols involving extensive ment, recombination and haplotype analysis, linkage dis- counseling and patient education (22). Most persons, in- equilibrium, physical mapping, and exon amplification, cluding those testing positive, state that they are relieved to were first developed or tested during the search for the HD know the results, and this knowledge enables them to face gene (12). Not all patients, however, Using exon amplification and cDNA cloning, the actual have had unequivocally positive experiences with testing gene (IT15 or huntingtin) was identified in 1993 (15). The central difficulty stems from the availability of a mutation proved to be an expansion of a CAG repeat, mak- presymptomatic test for a disorder with limited therapeutic ing HD a member of a group of similar triplet repeat disor- interventions (at present), a dilemma termed the Tiresias ders (9, 16-18). It spans a genomic region of more than 200 kb Repeat Length Instabilityand HD Clinical and is transcribed into two versions of mRNA, varying only Genetics in the length of their 3′ untranslated region, The open read- ing frame encodes a protein of about 350 kd with no signifi- Analysis of the triplet repeat has clarified the issue of new cant homology to known proteins (15,19). The previous belief, that new HD muta- tions do not occur, was disproved with the discovery of the HD repeat expansion. The lengths of normal repeats change Genetic Diagnosis in fewer than 1% of intergenerational transmissions; when Diagnosis of HD has been greatly simplified by the direct the length does change, it is typically by only one triplet. Previously, genetic diagnosis re- The frequency of changes in length increases with transmis- quired cumbersome linkage analysis, impossible if family sion of longer repeats and becomes appreciable for alleles members were not available or were not heterozygous for the with repeats of intermediate length (29 to 35 triplets). By contrast, the direct gene test, typically a ing paternal transmission, these alleles are more likely to single polymerase chain reaction, enables the length of the expand then to contract, and the change, unlike in normal repeat in each allele to be measured. The test is highly sensi- repeats, is often of more than one or two triplets. On occa- Chapter 125: Huntington Disease 1821 FIGURE 125. The age at which affected parents and their affected children first manifest disease symptoms is depicted as a survival curve. The younger generation is affected at a substantially earlier age. Correlation of repeat length with age at onset senblatt A, et al.

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A related and interesting definition: Aging represents a state of complex multifactorial pathways that involve and ongoing molecular discount 100 mg kamagra soft otc, cellular generic 100mg kamagra soft visa, and organ damage causing functional loss buy kamagra soft 100mg online, disease vulnerability and eventual death (Fontana et al, 2010). Memory loss is a less prominent feature of normal ageing than has sometimes been supposed. Healthy older people do not perform quite as well on objective memory tests as healthy younger people. However, normal aging does not cause functional decline, and ability to perform the normal activities of daily living is maintained. As we get older we slow down both physically and mentally. It takes longer to do normal tasks, including mental tasks like calculations and solving puzzles. It also takes longer to interpret new information, particularly visual-spatial information – which explains why older drivers have more accidents at intersections than on the open road. Executive function and the ability to put together the “big picture” also declines with age. This may explain why some people who have functioned in highly demanding roles are “perfectly happy”, in retirement, to occupy themselves with “odd-jobs about the house”. While these people may have filled their lives with many new activities, slowing down of mental functions and greater focus on details may also partly underpin this happy state of affairs. When people with mild cognitive problems are followed up for 5 years, 80% have developed dementia (Godinho et al, 2011). A recent study of people over 65 years found – cognitive impairment but no dementia, 14. The clustering of white matter lesions (WML) in the temporal region identifies individuals at increased risk of both mild-NCD or dementia (Mortamais et al, 2013). Apathy in mild-NCD and dementia is associated with abnormalities in the frontal regions and anterior cingulate (Stella et al, 2013). Evidence of mild cognitive decline from a previous level of performance in one or more cognitive domains (language, memory, social cognition etc) 1. Deficits to not interfere with capacity for independence (paying bills, medication – but greater effort and strategies may be necessary). Deficits not better explained by another mental disorder DEMENTIA Dementia (Latin, de- “away” + mens “mind”) causes distress to afflicted individuals and family members. It is costly for the community, and relatively unresponsive to current treatment. It is a common disorder and the prevalence is increasing. Dementia affects >1% of people aged 60-64, and the prevalence doubles every 5 years after 60 years of age, reaching 30-50% of people >85 years. The proportion of people surviving into old age is increasing, and it is this group which provides most cases of dementia. Dementia is a set of symptoms, and like cough and fever, this set of symptoms may result from various disorders/diseases. However, to meet diagnostic criteria, there must also be decline in one other area of cognition. The term cognition (Latin, cogito, “to think”) refers to the human processing of information, and includes domains such as language, praxis, gnosis, visuospatial ability and executive function. Particular types of dementia (vascular dementia, for example) have additional diagnostic criteria (focal neurological signs, in the case of vascular dementia). Other diagnostic systems place greater diagnostic importance on the presence of “global deterioration in function” (including self-care and activities of daily living). The “cognitive paradigm” is the view that memory and language disorders are the primary symptoms of dementia. However, recently much importance has been placed on the behavioural and psychological symptoms of dementia (BPSD) (Burns, 2009). The behavioural symptoms include screaming and wandering, the psychological symptoms include change in personality, delusions, hallucinations and depression. The BPSD present major management difficulties, and are frequently the main concern of carers. The degree to which BPSD are simply manifestations of cognitive impairment remains unclear (Savva et al, 2009). BPSD often characterise the different sub-types of dementia: vascular dementia (VaD), depression; Dementia with Lewy bodies (DLB), hallucinations and paranoid ideas; frontotemporal dementia (FTD), personality change; subcortical dementia, lack of initiation. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (language, memory, social cognition etc) 1. The cognitive deficits interfere with independence in everyday activities (paying bills, managing medication. Cognitive deficits interfere with independence in everyday activities D. Not exclusively in the context of delirium Treatable dementia Less than 5% of cases presenting with dementia have a treatable cause. These include: • Hypothyroidism • Vitamin B 1 deficiency • Vitamin B 12 deficiency • Normal pressure hydrocephalus • Space occupying lesion • Pseudodementia (depression presenting as dementia) Pridmore S. It accounts for at least 60-70% (Lovestone, 2000) of all cases of dementia, and the prevalence is 4-8% of people above 65 years of age (Jacobson et al, 2005). Alois Alzheimer (German; 1864-1915) described the first case of the disorder which bears his name: a middle-aged female who suffered cognitive loss, functional decline, delusions and hallucinations. At autopsy the brain was atrophied and microscopy revealed plaques and neurofibrillary tangles. While AD may occur in middle age, it is more common in old age. The clinical features reported by Alzheimer: cognitive and functional decline often combined with psychotic symptoms remain diagnostically important. The psychotic symptoms of AD are difficult to quantify, they vary with the stage of the disorder, and it can be difficult to communicate satisfactorily with demented people. It is probable that hallucinations and delusions occur in 10-50% of people with AD. Hallucinations are more often visual than auditory, and the delusions are usually that people are entering the house or things are being stolen. There is a loss of awareness and a reduced ability to respond to the environment – thus, a change in personality occurs. Relatives often complain about the loss of sensitivity and manners and increased impulsivity in the patient. Other behavioural problems include wandering (which make it difficult to keep the patient safe), altered sleep pattern (with more disturbed behaviour at night) and incontinence. Grunting and screaming may occur in the late stages. Classification – Early/Late Early-onset AD (EOAD) and late-onset (LOAD) are arranged around 65 years of age. They have different genetic contributions, and EOAD tends to have a more rapid course. Investigations • Urea and electrolytes • Thyroid function tests • B12 and folate • FBE • Syphilis serology • EEG (usually abnormal in early AD, in contrast to frontotemporal dementia) • CT (not considered essential) • SPECT (where regional dementias are suspected). SPECT studies have 90- 100% sensitivity in discriminating AD patients from healthy controls (Johnson et al, 1993). There is progressive loss of neurons and synapses with large numbers of extracellular amyloid plaques and intracellular neurofibrillary tangles. Plaques are composed of peptides called amyloid beta (Aβ). Aβ is a section taken from amyloid precursor protein (APP). APP is a normal structure which penetrates neuron membranes and is important in neuron growth and post-injury repair. In AD, APP is cut into smaller pieces, including pieces of Aβ, which come together as clumps as senile plaques in the extracellular space. Neurofibrillary tangles are composed of aggregation of tau protein. Neurons have an internal support structure of microtubules, which function as tracks, sending nutrients from the cell body along the axon and back. Tau is a protein which, when phosphorylated, stabilizes the microtubules. In AD the tau becomes hyper- phosphorylated and clumps together destroying the neuron transport system.

Technical and clinical success- branch fibrous renal artery disease buy cheap kamagra soft 100mg on-line, but long-term technical and es do not necessarily occur together because technical success clinical success rates are not available for PTRA of branch lesions m ay be apparent cheap kamagra soft 100mg without prescription, but without im provem ent in blood pressure due to fibrous dysplasia order kamagra soft 100mg free shipping. Atheroembolic renal failure Severity of hypertension Rupture of the renal artery Specific type of renal artery disease and threat to renal function Dissection of the renal artery General medical condition of patient Thrombotic occlusion of the renal artery Relative efficacy and risk of medical antihypertensive therapy, PTRA, Occlusion of a branch renal artery renal artery stenting, surgical revascularization Balloon malfunction (may lead to inability to remove balloon) Balloon rupture Puncture site hematoma, hemorrhage, or vessel tear Median nerve compression (axillary approach) FIGURE 3-49 Renal artery spasm Selection of treatm ent for patients with renal artery disease. In Mortality (≤1%) selecting treatm ent options for patients with renal artery disease, there are several factors to consider: what is the likelihood that the renal artery disease is causing the hypertension? For patients with fibrous renal artery disease the likelihood is high; for patients FIGURE 3-48 with atherosclerotic renal artery disease (ASO -RAD), the likeli- Com plications of translum inal angioplasty of the renal arteries. The m ore severe the The m ore com m on com plications of PTRA are contrast-induced hypertension, the greater the inclination to intervene with either acute renal failure (ARF) and atheroem bolic renal failure. For children, adolescents, and Dissection of the renal artery, occlusion of a branch renal artery, younger adults, m ost of whom will have fibrous renal artery dis- and occasionally throm botic occlusion of the m ain renal artery ease, intervention is usually recom m ended to avoid lifelong anti- m ay occur. In experienced hands, rupture of the renal artery is hypertensive therapy. M inor com plications relate prim arily to the puncture site. Som e of these com plications of percutaneous trans- renal angioplasty (PTRA), renal artery stenting, and surgical lum inal renal angioplasty, particularly atheroem bolic renal failure revascularization. Local experience and expertise of the treating and/or contrast-induced acute renal failure (ARF) m ay also be physicians m ust be considered as well in selection of treatm ent observed with renal artery stent procedures. Pohl M A: Renal artery stenosis, renal vascular hypertension and ischemic 11. Edited by Schrier RW , renal artery stenosis in patients with atherosclerosis elsewhere. Rim m er JM , Gennari FJ: Atherosclerotic renovascular disease and 12. Vetrovec GW , Landwehr DM , Edwards VL: Incidence of renal artery progressive renal failure. Jacobson H R: Ischem ic renal disease: an overlooked clinical entity? N ovick AC: Patient selection for intervention to preserve renal renal artery stenosis. London: W B Saunders; ovascular disease in hypertensive patients. Nally JV, Olin JW , Lammert M D: Advances in noninvasive screening for 16. Schreiber M J, Pohl M A, N ovick AC: The natural history of athero- renovascular hypertension disease. M ann SJ, Pickering TG: Detection of renovascular hypertension: state 11:383–392. Ying CY, Tifft CP, Gavras H , Chobanian AV: Renal revascularization hypertension and renal insufficiency: trends in m edical com orbidity in the azotem ic hypertensive patient resistant to therapy. N ovick AC, Pohl M A: Atherosclerotic renal artery occlusion extend- 18. In ing into branches: successful revascularization in situ with a branched H ypertension. The production of persistent elevation of systolic blood causing end-stage renal disease, incidence, clinical correlates, and pressure by means of renal ischemia. Am J Kidney D is 1994, M orris GC Jr, DeBakey M E, Cooley M J: Surgical treatm ent of renal failure 24:622–639. Appel RG, Bleyer AJ, Reavis S, H ansen KJ: Renovascular disease in older N ovick AC, Ziegelbaum M , Vidt DG, et al. Page IH : The production of persistent arterial hypertension by cellophane J Am Soc N ephrol 1998, 9:252–256. Adv N ephrol N ecker H osp correlation of renal arterial disease. Pohl M A, Novick AC: Natural history of atherosclerotic and fibrous renal Novick AC, Straffon RA, Stewart BH, et al. Goncharenko V, Gerlock AJ Jr, Shaff M I, H ollifield JW : Progression of Novick AC, Stewart R: Use of the thoracic aorta for renal revascularization. Hollenberg NK: M edical therapy of renovascular hypertension: efficacy and Textor SC: Renovascular hypertension. Curr O pin N ephrol H yperten safety of captopril in 269 patients. Pohl M A: M edical m anagem ent of renovascular hypertension. In Renal W orking Group on Renovascular H ypertension: Detection, evaluation, and Vascular D isease. Arch Intern M ed London: W B Saunders; 1996, 339–349. H ypertension stenoses with vascular endoprostheses after unsuccessful balloon 1989, 14:247–257. H ypertension stenting on progression of renovascular renal failure. H ypertension 1989, Pickering TG, Herman L, Devereux RB, et al. Angioplastie (EM M A) Study Group: Blood pressure United States Renal Data System Coordinating Center: Incidence and causes outcom e of angioplasty in atherosclerotic renal artery stenosis: of treated ESRD. Bethesda: USRDS Coordinating Textor SC: Revascularization in atherosclerotic renal artery disease Center; 1994:43–54. W einberger he adrenal gland is involved in the production of a variety of steroid hormones and catecholamines that influence blood Tpressure. Thus, it is not surprising that several adrenal disorders may result in hypertension. M any of these disorders are potentially curable or responsive to specific therapies. Therefore, identifying adrenal disorders is an important consideration when elevated blood pressure occurs suddenly or in a young person, is severe or difficult to treat, or is associated with manifestations suggestive of a secondary form of hypertension. Because these occurrences are relatively rare, it is necessary to have a high index of suspicion and understand the pathophysiology on which the diagnosis and treatment of these problems is based. Three general forms of hypertension that result from excessive produc- tion of mineralocorticoids, glucocorticoids, or catecholamines are reviewed in the context of their normal production, metabolism, and feedback systems. The organization of this chapter provides the background for understanding the normal physiology and pathophysiologic changes on which effective screening and diagnosis of adrenal abnormalities are based. Primary aldosteronism Autonomous hypersecretion Increased renal sodium and Extracellular fluid volume of aldosterone (hyperminer- water reabsorption, expansion, hypokalemia alocorticoidism) increased urinary (? A cross section of the norm al adrenal Zona before (left) and after (right) stim ulation with adrenocorticotropic glomerulosa horm one (ACTH ). The adrenal is organized into the outer adrenal cortex and the inner adrenal m edulla. The outer adrenal cortex is com posed of the zona glom erulosa, zona fasciculata, and zona reticularis. The zona glom erulosa is responsible for produc- Zona tion of aldosterone and other m ineralocorticoids and is chiefly fasciculata under the control of angiotensin II (see Figs. The zona fasciculata and zona reticularis are influenced prim arily by ACTH and produce glucocorticoids and som e androgens (see Figs. The adrenal m edulla produces catecholam ines and is the m ajor source of epinephrine (in addition to the organ of Zona Zuckerkandl located at the aortic bifurcation) (see Fig. The sequence of C=O C=O O adrenal steroid biosynthesis beginning with OH cholesterol is shown as are the enzymes responsible for production of specific steroids. Note that aldosterone production nor- Pregnenolone 17-Hydroxypregnenolone Dehydroepiandrosterone mally occurs only in the zona glomerulosa (see Fig. Aldosterone and cortisol and their respective major stimulatory ACTH factors, plasma renin activity (PRA) and adrenocorticotropic hormone (ACTH), demonstrate circadian rhythms. The lowest values for all of these components are normally seen during the sleep period when the PRA need for active steroid production is minimal. ACTH levels increase early before awakening, stimulating cortisol production in prepara- Aldosterone tion for the physiologic changes associated with arousal. PRA increas- es abruptly with the assumption of the upright posture, followed by an increase in aldosterone production and release. Both steroids Cortisol demonstrate their highest values through the morning and early after- noon.

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In the a secondary analysis of a large-scale disability survey in the study by Kavanagh and Knapp (23) buy 100mg kamagra soft fast delivery, the costs of people with United Kingdom buy 100mg kamagra soft amex, disabled elderly people with more severe disabilities cheap kamagra soft 100mg amex, but no cognitive disability, were approximately cognitive disability received more intensive care and were $25,299. The additional costs of people with cognitive dis- referred more often to health care services (23). In an analysis of Canadian data (27) in which a bivariate The studies by Souetreˆ et al. The study by Ernst and Hay (32) Mental State Examination (MMSE) scores was associated estimated the net costs of care from aggregate data sets and with an average increase in costs of $1,343 (Canadian dol- surveys. Even when informal care time was valued by using industrial aggregate wage levels rather than mini- mum wage levels, the relationship between severity and costs Evidence of Cost-Effectiveness remained statistically significant. The relationship between costs of care and severity of disease is complex. Increases in It is clear that the costs of health and social care and informal the costs of care as disease becomes more severe represent care for people with AD is high, and evidence suggest that in part a greater use of institution-based care as people be- the costs increase with the severity of cognitive disability come more cognitively and functionally disabled by their and need for long-stay care or institutional care. They may also reflect aging and the effect of comor- argued that it might be rational to support the introduction bidities (23). In addition, informal carers age and may be of drug treatments to slow down the progression of the affected by declining health and less ability to provide care. This would lead to a saving of costs to offset the acquisition costs of the drugs. However, this proposal has been criticized on Setting of Care the grounds that it would shift the burden of the disease An important determinant of the costs of health and social from the public sector budget to private citizens, without care is the distribution of people with AD by setting of care. A full evaluation For most of the studies reported in Table 89. The exceptions to this are the study by have been published to assess the relative value for money Gray and Fenn (7), in which the costs of long-stay care of tacrine, donepezil, and rivastigmine. The details of the methods used and comparators of the studies. Only four meet the of cognitive and functional disability, the presence of other criteria for full economic evaluations, and these are shown health problems, the ability of informal carers to support in Table 89. The four studies analyzed the same drug the proportion of people cared for in long-stay care settings treatment (donepezil) in four different countries/settings: is between 6% and 53% for people with mild to moderate United Kingdom (37), Canada (38), United States (39), disease and 33% to 86% for people with severe disease. In the regression analysis by a hypothetical cohort of people with nonsevere AD (MMSE Holmes et al. For each additional year of age of the carer, the costs Despite differences in the provision of health care be- of institutional care were predicted to increase by roughly tween the United Kingdom, the United States, and Canada, $264 per year. FULL ECONOMIC EVALUATIONS OF DRUGS FOR ALZHEIMER DISEASE Incremental Year of Original Cost (Health Study Outcome Measure Costing Currency PPP$, 1996) Health Gain Stewart et al. Three studies found QALY data were collected alongside a cross-sectional study, that the distribution of severity states of patients is the most which means that no information was obtained on how the important variable affecting the cost-effectiveness of drugs. In addition, the sample of patients used to liminary and uncertain and that a number of issues must elicit utility values may have been unrepresentative of the be considered when the results are interpreted. There were also poten- tial problems with the use of proxy respondents. However, given the cognitive and behavioral degenerative process as- Costs sociated with AD, the use of alternative respondents may be unavoidable. Additionally, measuring outcomes as 'time First of all, no prospective measurement of resource use spent in less than severe state' does not inform health and associated with the drug or usual care was made. Costs were social care decision makers about the value of quality of life estimated from retrospective analysis of available data sets for people with AD and their family and carers. The range of cost items Effectiveness and the costing methodologies employed in each study were heterogeneous. Some of these Three analyses (37,38,49) directly or indirectly associ- trials have been criticized elsewhere (50) for having enrolled ated the dynamic of treatment costs with the progression a carefully selected subgroup of patients with mild-to-mod- of disease severity, measured with the MMSE. The MMSE erate AD and excluded those with coexisting illness or con- score was shown to be strongly correlated with costs of de- current treatment. In real practice, the eligible population mentia care, but it is unclear to what extent the use of may be considerably different. Consequently, only a limited this instrument is robust in modeling studies. It has been proportion of people may be adequately and safely treated. The cost-effec- tiveness of cholinesterase inhibitors depends on the distribu- Outcome Measures tion of patients across different severity states (38). In this context, the correct assessment of the duration of the treat- One study used QALYs to measure the benefits derived ment effect of anticholinesterase drugs assumes a central from introducing the drug (39). In the other studies, bene- role because it affects the number of people having mild- fits were measured in terms of 'time spent in condition less to-moderate AD at any one time. Modeling However, this instrument has not been validated in patients with AD, and its ability to detect small improvements in Some authors have recently challenged the use of Markov potentially important clinical aspects is doubtful. The models in the evaluation of antidementia drugs (33,48). Given the considerable context largely characterized by uncertainty surrounding the uncertainty surrounding the available data, deterministic value of the key variables, modeling techniques can be used models in which simplistic sensitivity analysis techniques to assess the value for money of new management strategies are used may not be adequate to assess the robustness of for the treatment of AD and compare them with the alterna- the results. The application of stochastic models allows the tive policy options. Further primary and secondary research uncertainty associated with relevant parameters of a model is required to provide robust estimates of the formal and to be incorporated and quantified. CONCLUSION REFERENCES As a direct consequence of changes in the age structure of 1. The epidemiologically based disorder focuses on assisting patients in their daily activities needs assessment reviews. The impact of the symptoms residential or nursing home care. In: Wimo A, Jonsson B, Karlsson trigger the need for long-term institutional care, including G, et al. Chichester: John the age of family carers, the behavioral problems of patients, Wiley and Sons, 1998. Institutionalization has been identified review of the disease, its epidemiology and economic impact. Some clinical evidence indicates that anticholinesterase 8. If the drugs are effective in controlling symp- 167–173. Canadian Study of Health and Aging: toms or slowing progression of the illness, they may delay study methods and prevalence of dementia. Can Med Assoc J the need for intensive support or institutionalization of pa- 1994;150:899–913. The high acquisition cost of the drugs, however, has 10. Prevalence of medically significant number of studies addressing the issue of costs diagnosed dementia in a defined United States population: Roch- and patient benefits. To date, a conclusive analysis has not clarified the most 12. The prevalence of demen- appropriate management strategy for the disorder. In the tia: a quantitative integration of the literature. Acta Psychiatr near future, new drugs for the treatment of AD are expected Scand 1987;76:465–479. Cochrane able to compare them in a clear and well-defined framework. In addition, if economic evaluation is to inform health and 14. Ox- impact of new interventions in practice, an estimation of ford: Update Software. 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In addition to regulating the peptide At a systems level 100mg kamagra soft overnight delivery, context-dependent sensitization in an- precursor gene buy kamagra soft 100mg amex, prodynorphin cheap kamagra soft 100 mg line, D1 receptor-mediated stim- imal models and cue-conditioned relapse in humans sug- ulation of CREB induces a large number of immediate early gests that the brain stores specific patterns of drug-related genes (IEGs)including several that encode transcription fac- information. Homeostatic responses that increase or de- tors, including c-fos, fras, junB, and zif268 (61–64). One crease the gain on the overall responsiveness of dopami- interesting finding is that one CREB regulated transcription nergic or other neurotransmitter systems in the brain could factor, FosB, a truncated isoform of Fos B has a long half- not mediate selective responsiveness to specific contexts or life compared to all other members of the Fos family of cues. Thus, general homeostatic mechanisms are not ade- transcription factors. Unlike other members of the Fos fam- quate to explain these phenomena. Elsewhere it has been ily, FosB is only slightly induced by acute stimulation, argued that core features of addiction arise from the inap- but because it is long lived, it begins to accumulate with propriate recruitment of molecular mechanisms normally repeated stimulation, including repeated administration of responsible for associative learning (37). Thus, long-term, but not short-term, persistence of drug addiction reflects the persistence of the administration of cocaine, amphetamine, opiates, nicotine, memory for this learned experience in the form of altered or PCP induces FosB in the NAc and dorsal striatum. Accumulation of FosB represents a molecular motes activation of the transcription factor CREB (59,73) mechanism by which drug-induced changes in gene expres- and a transient burst of altered gene expression (74). The sion can persist for weeks—even after drug use has been induction of multiple transcription factors by this mecha- discontinued. The biological significance of FosB induc- nism has already been described. Other psychostimulant tion will be better understood following identification of the induced IEG products that have been described in the stria- genes that it regulates. Certain AMPA glutamate receptor tum include homer-1a, narp, arc, and many others (62,74, subunit-encoding genes are among the candidates. Some of the genes induced by dopamine and psycho- though FosB is stable, it is ultimately degraded; thus, by stimulants in the striatum have been hypothesized to play Chapter 96: Molecular and Cellular Biology of Addiction 1377 a role in hippocampal LTP, making it tempting to speculate only a few situations, such as somatic dependence on op- that they may ultimately have a role in synaptic remodeling iates. Even for more difficult problems, however, powerful in the striatum (76–79). Indeed, D1 receptors have been tools are on the horizon. It is imperative, for example, to shown to be required for normal hippocampal long-term investigate the mechanisms by which dopamine excess potentiation (LTP), an important model of synaptic plastic- might produce long-lived pathological associative memories ity. For LTP in the CA1 region of the hippocampus to that could underlie compulsive drug use and late relapse. The requirement for activation of gene these reagents, we will be limited only by our neurobiologi- expression seems to be transient, because blockers of tran- cal imaginations. Activators of the cAMP cascade, REFERENCES including D1 agonists, can induce L-LTP (84,85). D1 re- ceptor blockade inhibits hippocampal L-LTP (85–87), and 1. The biological, social D1-knockout mice do not show L-LTP (88). Therefore, and clinical bases of drug addiction: commentary and debate. D1 receptor activation in the hippocampus may act to gate 2. Drugs abused by humans preferentially synaptic plasticity, helping to determine whether changes increase synaptic dopamine concentrations in the mesolimbic in synaptic strength are long lasting or merely transient. Proc Natl Acad Sci USA 1988;85: A role for dopamine receptors in the modification of 5274–5278. MK-801 (dizocilpine): synergist and conditioned stimulus in bromocriptine-induced extracellular dopamine can act as a reinforcement learning psychomotor sensitization. From synapse to vesicle: the reuptake and depression)is found at corticostriatal synapses in vivo (90) storage of biogenic amine neurotransmitters. Some groups have found that striatal Acta 1993;1144:249–263. Hyperlocomotion and indiffer- LTP can be modified by dopamine receptor stimulation ence to cocaine and amphetamine in mice lacking the dopamine (91,93,94). Moreover, based on genetic manipulations, transporter. CREB has been implicated in both invertebrate and verte- 6. Altered brain serotonin brate models of synaptic plasticity and long-term memory homeostasis and locomotor insensitivity to 3,4-methylenedioxy- (80–82,95). Moreover, changes in striatal synaptic physiol- methamphetamine ('Ecstasy')in serotonin transporter-deficient mice. At the systems level, dorsal re- norepinephrine transporter are supersensitive to psychostimu- gions of striatum appear to be involved in the learning and lants. Cocaine self- particularly in response to external cues. Ventral striatal administration in dopamine-transporter knockout mice [see com- ments] [published erratum appears in Nat Neurosci 1998;1(4): areas are involved in acting on the motivational significance 330]. Opioids excite dopamine neurons by regions may contribute to drug use through consolidation hyperpolarization of local interneurons. J Neurosci 1992;12: of drug-taking and -seeking behaviors. Destruction of dopa- mine in the nucleus accumbens selectively attenuates cocaine but of genes transiently induced by addictive drugs, the products not heroin self-administration in rats. Psychopharmacology (Berl) of which produce stable remodeling of synapses. Heroin and cocaine intravenous self-administration in rats: mediation by separate CONCLUSION neural systems. Disruption of cocaine and heroin self-administration following kainic acid lesions of All of the initial molecular targets of drugs of abuse have the nucleus accumbens. Pharmacol Biochem Behav 1985;23: been characterized and cloned. Blockade of nucleus accum- zation, and most important, compulsive drug use, and late bens opiate receptors attenuates intravenous heroin reward in the rat. Molecular genetic analysis of the role of GABAergic has been made in identifying large numbers of molecular systems in the behavioral and cellular actions of alcohol. Behav changes initiated by drugs of abuse, but coherent biological Genet 1996;26:313–323. Ethanol enhances 1378 Neuropsychopharmacology: The Fifth Generation of Progress the release of dopamine and serotonin in the nucleus accumbens 38. Alcohol Clin Exp Res 1992;16: phine tolerance on the paw-pressure and tail-shock vocalization 781–785. GABAA receptor antagonism in the ex- pensatory responding. Psychopharmacology (Berl) 1999;145: tended amygdala decreases ethanol self-administration in rats. The phasic reward signal of primate dopamine neu- 17. Naltrexone in the treatment of alco- Res Rev 1993;18:247–291. Addictive drugs as reinforcers: multiple partial ac- 20. Molecular and cellular basis of addic- Trends Pharmacol Sci 1997;18:54–59. Reduction of mor- sumption in null mutant mice lacking 5-HT1B serotonin recep- phine abstinence in mice with a mutation in the gene encoding tors. Genetic analysis of drug addiction: mine lesions on the locomotor stimulant action of nicotine in the role of cAMP response element binding protein. Alteration of GABAA nucleus accumbens and similarity to those of addictive drugs [see receptor alpha 1-subunit mRNA in mouse brain following con- comments]. Ethanol and neurotransmit- tors containing the beta2 subunit are involved in the reinforcing ter interactions—from molecular to integrative effects. Ethanol withdrawal is associated with nicotinic receptor subunit in nicotine-elicited locomotion, dem- onstrated by in vivo antisense oligonucleotide infusion. Neurore- increased extracellular glutamate in the rat striatum. Cocaine addiction: psychology and neurophysiology linergic and opioid receptor mechanisms in nicotine- induced [published erratum appears in Science 1991;253:494]. Drug abuse: hedonic homeostatic dysreg- Neuropsychiatry Clin Neurosci 1997;9:482–497.

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