By W. Sigmor. Saint Francis College, Loretto, Pennsylvania.

Villemagne VL trusted amitriptyline 50 mg postpartum depression definition who, Wong DF buy 75mg amitriptyline free shipping anxiety medication list, Yokoi F, Stephane M, Rice KC, Matecka D, Clough DJ, Dannals RF, Rothman RB. GBR12909 attenuates am- phetamine-induced striatal dopamine release as measured by continuous infusion PET scans. The fourth method in which neuroreceptor imaging can assist in drug development is the empirical evaluation of theories of disease, such as the DA hypothesis for schizo- phrenia. For example, Grace (1991) (121) proposed that schizophrenia is characterized by intrasynaptic concentra- tions of DA that are abnormally low in the basal tonic state and abnormally high in the simulated phasic state. This has been supported by numerous findings of elevated dopa GBR 12909 (mg/kg) 18 decarboxylase measurements using [ F]fluorodopa (122), FIGURE 34. This histogram illustrates the percentage dopa- elevated amphetamine induced dopamine release mine transporter (DAT) occupancy by GBR 12909 (GBR) as mea- suredby positronemissiontomographyimaging with[11C]WIN35, (123–125), and elevated D2Rs (97,126). DAT occupancy is represented as the percentage mean potential evidence that elevated intrasynaptic dopamine re- standard error of the mean differences between binding poten- lease is also found at baseline (126–128). In this example tials at baseline and after GBR administration. Percentage occu- pancy is calculated by the formula as follows: [(Baseline binding of the DA system, the combined strength of measuring pre- potential GBR binding potential)/Baseline binding potential] synaptic, postsynaptic, and intrasynaptic DA, for example, 100. Inset: Relation between DAT occupancy and GBR dose provides converging evidence to test this hypothesis. Modified from Villemagne V, Rothman RB, Yokoi F, Rice KC, Matecka D, Dannals RF, Wong DF. Doses of GBR12909 that opment of additional ligands such as those for glutamate, suppress cocaine self-administration in nonhuman primates sub- glycine, and second messengers, will further expand the po- stantially occupy dopamine transporters as measured by [11C]WIN35, 428 PET scans. Copyright  tential to evaluate the complex pathophysiology of schizo- 1999, Wiley-Liss, Inc. Chapter 34: Proof of Concept 467 half-lives (131), although the sensitivity allows only micro- molar measures in contrast to the nanomolar measures at- tained with PET. These methods have also been employed in animal models using [19F]nuclear magnetic resonance (NMR) chemical shift imaging to study the cerebral distri- bution of general anesthetics in vivo (132). MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) provides surrogate markers for disease progression to facilitate drug develop- A ment. For example, T2-weighted cerebral MRI functions as a surrogate marker in early stages of demyelinating disease to predict disease progression and disability over the subse- quent 10 years (132a–132e). Another example of the use of MRI as a surrogate marker for drug development is in the diagnosis and treatment of subjects with AD. Atrophy of the hippocampal formation has been correlated with memory and cognitive impair- ments. Reductions in the volume of the hippocampus have been predictive for the individuals who later develop mem- ory impairments consistent with AD (133). Another marker of the vulnerability to develop AD is the measure of the B apolipoprotein E (APOE) genotype. These histograms contrast the release of DA after AD is increased for people with the gene (134). The APOE administration of amphetamine (AMP) in Papio anubis baboons gene is associated with loss of hippocampal volume (135). For each histo- Cross-sectional studies in 116 healthy volunteers, 59 to 85 gram, the abscissa indicates the intravenous administration of saline (3 mL/kg) (PRE AMP) or amphetamine (1 mg/kg) (POST years old, demonstrated significantly larger ventricular vol- AMP) and the ordinate is the average volume of distribution (Vh) umes and smaller gray and white matter volumes in older and the standard error of the mean.

Using the phenomic approach order amitriptyline 50mg otc depression symptoms types, the behav- the disorder may be modeled in transgenic mice or in other ioral phenotype of Rett syndrome (17) effective amitriptyline 75mg anxiety icd 9 code, with its characteris- species. The canine model of narcolepsy (20) genetic origin was recognized. Moreover, the phenomic ap- is an interesting example of an approach to a human clinical proach does not discount acquired disorders, such as fetal disorder. Mutations for canine, autosomal recessive, narco- alcohol syndrome, as having behavioral phenotypes. The lepsy were identified by linkage analysis in canine back- impact of alcohol on cellular signaling is now well known, crosses, and homology was demonstrated between human with its consequences of cell death, abnormal midline brain chromosome 6 and canine chromosome 12. Canine narco- development, behavioral problems, and learning disabilities lepsy is caused by a disruption of a G-protein–coupled re- (16,23). However, human narcolepsy is not as- following definition that includes the characteristic types sociated with frequent hypocretin gene mutation (20). This does not mean that the behavior is present in all instances but that the probability of its occurrence is PSYCHOPATHOLOGY AND BEHAVIORAL increased. In the future, more may be learned about brain PHENOTYPES mechanisms by comparing persons with behavioral involve- ment with others who have the same syndrome but without Numerous neurogenetic disorders are associated with non- the behavioral features. Although some investigators have sought to limit the These include attention problems, hyperactivity, impulsiv- study of behavioral phenotypes to known genetic disorders ity, self-injury, aggression, autistic-like behavior, and pre- (11), knowledge of the genetic disorder is only the first step. Such presentations indicate vulnerabil- Links from gene to behavior are complicated in that one ity of the developing brain and perturbation of brain systems gene may lead to the encoding of many, perhaps ten or resulting in these clinical conditions. However, because more, different proteins; the number of genes and type of these behaviors occur across many syndromes, they lack mutation determine complexity. For example, in LND, the specificity and do not qualify as specific behavioral pheno- 628 Neuropsychopharmacology: The Fifth Generation of Progress types. Still, these behavioral features should be included in are highlighted, findings on origin are discussed, and poten- the description of the disorders. For example, the relation- tial neurochemical and neuroanatomic abnormalities are re- ship between aggression and antisocial behavior has been viewed. Behavioral and pharmacologic therapies have had suggested in monoamine oxidase A (MAOA) deficiency. Neuroanatomic studies, brain imaging studies, single large Dutch kindred (21). The affected males differed and continuing investigations of neurotransmitter systems, from unaffected males in that they tested in the borderline endocrine rhythms, and sleep studies may provide informa- range of mental retardation and demonstrated increased im- tion that will be helpful in the future in treatment. Yet a specific psychiatric diagnosis was not made in four affected males who were examined Lesch–Nyhan Disease by psychiatrists. Because MAOA deficiency leads to in- LND is a rare (1:380,000) sex-linked recessive disease creased 5-hydroxytryptamine (5-HT) levels, the aggressive caused by an inborn error of purine nucleotide metabolism. HPRT, which is involved in the purine salvage (purine base suggested that even if a possible association between MAOA recycling) pathway (25). LND is of psychosocial and psychiatric tors noted that genes are essentially simple and code for importance because of the lifelong suffering experienced by proteins, whereas behavior is complex; thus, a direct causal the involved child and his family, the uniqueness of the relationship between a single gene and a specific behavior behavioral phenotype, and the resources needed for lifelong is highly unlikely. In MAOA deficiency, complexity is patient supervision. Moreover, an understanding of the neu- shown by the variability in the behavioral phenotype and robiological basis of this disease may contribute to a better by the highly complex consequences of MAOA deficiency understanding of brain mechanisms involved in self-inju- on neurotransmitter function. Thus, the full pathway from rious and compulsive behaviors. Still, a great deal may be learned by considering such path- Genetic and Metabolic Aspects ways in neurogenetic syndromes. The HPRT-encoding gene is located on the X chromosome in the q26-q27 region and is made up of nine exons and eight introns totaling 57 kilobases (kb).

The natural abundance of the 13C isotope is This chapter reviews these findings and discusses some of 1 order amitriptyline 10mg online bipolar depression 0f. Substrates labeled with for studying neurotransmitter systems of approximately 1 13 to 4 mm3 in animal models and 7 to 40 mm3 in human the nonradioactive purchase 50mg amitriptyline amex anxiety 78749, stable, C isotope have been employed in vivo to study metabolic flux, enzyme activity, and meta- brain. Even in the best case the MRS signal is the sum of bolic regulation in the living brain of animals and humans the signal from a large number of neurons and glia including (6–39). Enhanced sensitivity may be achieved by measuring many different subtypes. Fortunately, nature has localized the 13C enrichment of a molecule through indirect detection key enzymes and metabolites involved in neurotransmitter through 1H MRS. From these measurements the flux cycling in specific cell types, which greatly simplifies the through specific metabolic pathways may be calculated (17, interpretation of the MRS measurements. As with any new tech- and the relationship of amino acid metabolism to functional nique there are still uncertainties due to methodologic is- neuroenergetics. Studies performed to validate the MRS measurements glutamine have been shown to be localized within gluta- will be reviewed, and present limits in measurement accu- matergic neurons, GABAergic neurons, and glia, respec- racy and interpretation delineated. Under nonfasting conditions glucose is the almost exclusive source of energy for the brain. By following the flow of 13C label from glu- 13 IN VIVO C MRS MEASUREMENTS OF THE cose into these metabolites, MRS has been used to deter- PATHWAYS OF GLUCOSE OXIDATION: mine the separate rates of glucose oxidation in these cell FINDINGS AND VALIDATION types. The metabolism of glutamatergic neurons, GABAer- gic neurons, and glia is coupled by neurotransmitter cycles. This section reviews studies in which MRS was used to In the glutamate/glutamine cycle, glutamate released from measure the pathways of glucose oxidation in the cerebral nerve terminals (by either vesicular release or transport re- cortex. Glucose oxidation under nonfasting conditions is versal) is transported into surrounding glial cells, and con- almost the exclusive source of energy for the brain. Glutamine in then transported out of localization of key enzymes involved in GABA and gluta- the glia and into the neurons, where it is converted back mate metabolism in specific cell types provides the capabil- to glutamate, thereby completing the cycle (Fig. By ity for MRS to study their separate neuroenergetic require- following the flow of 13C label from glutamate into gluta- 13 ments. Through a similar strategy the cal specificity of MRS allows the flow of 13C label from GABA/glutamine cycle may be measured. The major finding of these stud- cycling to neuroenergetics have provided several new and ies is that in normal conditions in nonactivated human cere- controversial insights into the relationship of brain metabo- bral cortex and in rodent models, glucose oxidation in gluta- lism and function. Contrary to the previous view of a sepa- matergic neurons accounts for between 60% and 80% of rate metabolic and neurotransmitter pool of glutamate, glu- cerebral cortex energy consumption. The remaining 20% tamate release and recycling have been shown to be a major to 40% is primarily distributed between GABAergic neu- metabolic pathway. Another key finding is that the gluta- mate/glutamine cycle in the cerebral cortex is coupled in a Oxidation in Glutamatergic Neurons close to 1:1 ratio to neuronal (primarily glutamatergic) glu- The initial use of MRS to study brain metabolism was to cose oxidation above isoelectricity. This finding, in combi- measure glucose oxidation by following the flow of 13C nation with cellular studies, has led to a model for the coup- isotope from [1-13C] glucose into the C4 position of gluta- ling between functional neuroenergetics and glutamate mate (2,6). The coupling between neurotransmis- a [1-13C] glucose precursor to C4-glutamate and subse- sion and neuroenergetics provides a linkage between the quently C4-glutamine. Glucose is metabolized to pyruvate functional imaging signal and specific neuronal processes. The 318 Neuropsychopharmacology: The Fifth Generation of Progress The rate of neuronal glucose oxidation has been deter- mined in several studies from 13C MRS and 1H-13CMRS measurements of cerebral cortex glutamate turnover from a [1-13C] glucose precursor in animal models (2,14–17, 21,22,25–27) and humans (12,13,18,19,29,31,35,43,44). Comparison of the rates of neuronal glucose oxidation mea- sured in these studies with conventional arteriovenous (AV) difference and PET measurements of total glucose con- sumption found that the majority (between 70% and 90%) of total glucose oxidation in the rat and human brain is associated with the large glutamate pool, believed to reflect glutamatergic neurons, measured by MRS. In two recent 13C MRS studies of resting awake human occipital parietal FIGURE 25. The figure shows a 50- cortex, in which other pathways of glucose metabolism were minute accumulation 13C MRS spectrum obtained at 4 T approxi- directly measured, a similar range of between 60% (35) and mately 60 minutes after the start of a 1-13C glucose infusion.