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Another problem is that generic 50 mg minocycline with mastercard, even in studies showing a reduction in transporter density buy generic minocycline 50 mg online, there are no consistent changes in 5-HT uptake. More recently, research has been directed towards a search for genetic polymorphisms of the 5-HT transporter gene that might account for disorders including depression, bipolar disorder, anxiety, substance abuse and autism. So far, no certain links with either the expression of, or vulnerability to, any disorder have emerged. One drug that seems to cause quite marked, long-term changes in 5-HT transporter function is MDMA. Interestingly, fenfluramine, another 5-HT-releasing agent, does not seem to have this effect. It has been suggested that loss of transporters in users of MDMA is due to the death of 5-HT neurons and that this is evidence for its neurotoxic effects. This toxicity is thought to be mediated by the formation of quinones and then free radicals from the metabolites of MDMA, although there are alternative explanations (see Sprague, Everman and Nichols 1998) and some individuals still dispute that this drug is actually neurotoxic in humans. At the very least, there is accumulating evidence for long-term deficits in cognitive and neuroendocrine function in users of MDMA and, of even greater concern, it is not known whether these are reversible. METABOLISM 5-HT is metabolised primarily by MAO to 5-hydroxyindoleacetic acid (5-HIAA) (Fig. In vitro, 5-HT is the preferred substrate for the MAOA, rather than the MAOB isoenzyme (see Chapter 8) and this appears to be the case in vivo since MAOA, but not MAOB, knock-out mice have increased concentrations of 5-HT in the brain. Obviously, because of its indole nucleus, 5-HT is not a substrate for the enzyme COMT which metabolises the catechol derivatives, dopamine and noradrenaline. However, other metabolic products of 5-HT are theoretically possible and one, 5-hydroxytryptophol, 5-HYDROXYTRYPTAMINE 197 which results from the reduction of its intermediate metabolite, 5-hydroxyindoleacetal- dehyde, instead of oxidation to 5-HIAA, has been identified in the brain. The comparatively straightforward link between 5-HT and its primary metabolite, 5-HIAA, encouraged many researchers to use changes in the ratio of tissue concentrations of 5-HIAA and 5-HT as an index of the rate of release of 5-HT ex vivo. However, it has been clear for some time that the majority of 5-HT is metabolised in the cytoplasm by MAO before it is released from 5-HT nerve terminals. Consequently, the reliability of the 5-HIAA:5-HT ratio as an index of transmitter release is rather dubious, although it could be used as an acceptable measure of MAO activity. In any case, the development of in vivo microdialysis means that changes in the concentration of extracellular 5-HT can now be monitored directly which, under drug- free conditions, provides a far more reliable indication of any changes in the rate of release of 5-HT. RECEPTORS Over the last 20 years, the development of receptor-selective ligands, coupled with advances in molecular biology, has resulted in the number of 5-HT receptors increasing from a modest two (identified by Gaddum and Picarelli in 1957) to the 14 recognised to date (Table 9. These form seven distinct families which, with the exception of the 5-HT3 receptor, are all G protein-coupled with seven transmembrane-spanning domains. Apart from 5-ht1E, 5-ht1F, 5-ht5 and 5-ht6 subtypes, for which genes have been identified, even though the native receptor protein remains elusive (hence their lower- case nomenclature), all are expressed in the CNS. All the native 5-HT receptors characterised so far are found postsynaptically, with respect to 5-HT terminals, and some are located presynaptically where they regulate the firing rate of 5-HT neurons and/or release of transmitter from their terminals. There is also evidence that some regulate the release of other transmitters in the terminal field and so could act as 5-HT heteroceptors. For instance, 5-HT1B receptor agonists inhibit K‡-evoked release from synaptosomes preloaded with either [3H]dopamine, [3H]nor- adrenaline, [3H]prolactin or [3H]glutamate. Apart from regulating neuronal firing and transmitter release, activation of certain 5-HT receptors with selective ligands causes specific behavioural or physiological changes (Table 9. There is also some evidence that 5-HT1A receptors, at least, might influence gene expression and neurogenesis and so they could have far-reaching effects on brain function. Essential features of the different receptor subtypes are highlighted here and, except where indicated, references to specific points can be found in the definitive review of this subject by Barnes and Sharp (1999). They are negatively coupled, via Gi/o/z proteins, to adenylyl cyclase such that their activation reduces production of cAMP. In turn, this leads to an increase in K‡ conductance and hyperpolarisation of 198 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION 5-HYDROXYTRYPTAMINE 199 Table 9. The importance of this action, as a possible explanation for the delay in the therapeutic effects of those antidepressants that increase the concentration of extracellular 5-HT, is discussed in Chapter 20. There is some evidence that pre- and postsynaptic receptors do not respond in exactly the same way to drug challenges and it has even been suggested that they are not identical. For instance, the drug BMY 7378 behaves as an agonist at presynaptic 5-HT1A receptors but has a low intrinsic activity at the postsynaptic site where it acts as an antagonist. However, there is as yet insufficient evidence to claim that there are subtypes of this receptor and, in any case, differences in the receptor reserve at pre- and postsynaptic sites could well explain some of the apparently conflicting findings.

It is uncertain to what extent specific but the age may range from 9 to 13 years order minocycline 50 mg free shipping. Approximately 3 years dimorphisms of the sexes are genetically determined through are required after the appearance of breast buds for maturation of hormonal action or influenced by environmental (including cul- tural) factors generic 50 mg minocycline free shipping. Developmental © The McGraw−Hill Anatomy, Sixth Edition Development Anatomy, Postnatal Companies, 2001 Growth, and Inheritance 780 Unit 7 Reproduction and Development FIGURE 22. A male has proportionately longer appendages and a longer neck than a female. The shape of the adult body is determined primarily by the Some of the physical and behavioral characteristics of skeleton and attached muscles, and also by the subcutaneous each stage of human growth and development are summarized connective tissue (especially adipose tissue) and extracellular in table 22. Although the body proportions of adult males and Physical anthropologists have long been interested in the females vary widely between individuals (fig. Mean data for body composition are summa- index, for example, is the breadth of the skull expressed as a per- rized in table 22. Developmental © The McGraw−Hill Anatomy, Sixth Edition Development Anatomy, Postnatal Companies, 2001 Growth, and Inheritance Chapter 22 Developmental Anatomy, Postnatal Growth, and Inheritance 781 TABLE 22. Oleson, “Body Composition in Normal Adults” in Human Body Composition, Vol. Knowledge Check People of African ancestry, for example, have comparatively long 20. Construct a table that lists the periods of postnatal growth appendages relative to sitting height; moreover, the forearm and from infancy through adolescence and indicate the events leg are long relative to the brachium and thigh (fig. People of African ancestry also have the nar- rowest pelvic girdle for a given shoulder width. Define the terms puberty, pubescence, sexual dimorphism, ancestry have relatively short appendage lengths to sitting and menarche. These differences provide distinct advantages and disad- brings it about? Com- track events, particularly the sprints and high hurdles, whereas pare the body structure of an adult female to that of an whites are generally adapted to distance running. Developmental © The McGraw−Hill Anatomy, Sixth Edition Development Anatomy, Postnatal Companies, 2001 Growth, and Inheritance 782 Unit 7 Reproduction and Development (a) (b) FIGURE 22. The first 22 pairs of chromo- somes are called the autosomal chromosomes. The photographs of two Olympic 400-meter runners have been scaled so that both have the same sitting height. This does not produce 46 dif- ferent chromosomes; rather, it produces 23 pairs of homologous chromosomes. Each member of a homologous pair, with the im- INHERITANCE portant exception of the sex chromosomes, looks like the other and contains similar genes (such as those coding for eye color, Inheritance is the acquisition of characteristics or qualities by height, and so on). These homologous pairs of chromosomes can transmission from parent to offspring. Hereditary information is be karyotyped (photographed or illustrated) and identified, as transmitted by genes. The twenty-third pair of chromosomes are the sex Objective 20 Explain how probability is involved in chromosomes, which may lookdifferent and may carry different predicting inheritance and use a Punnett square to illustrate genes. In a female these consist of two X chromosomes, whereas selected probabilities. Genes and Alleles Genetics and inheritance are important in anatomy and physiol- A gene is the portion of the DNA of a chromosome that con- ogy because of the numerous developmental and functional dis- tains the information needed to synthesize a particular protein orders that have a genetic basis. Although each diploid cell has a pair of genes for each and diseases are inherited finds practical application in genetic characteristic, these genes may be present in variant forms. The genetic inheritance of an individual begins with Those alternative forms of a gene that affect the same character- conception. Developmental © The McGraw−Hill Anatomy, Sixth Edition Development Anatomy, Postnatal Companies, 2001 Growth, and Inheritance Chapter 22 Developmental Anatomy, Postnatal Growth, and Inheritance 783 TABLE 22. Homologous chromosomes contain genes for the same characteristic at the same locus. One allele of each pair originates from the female parent and the other from the male. The shape of a person’s ears, for example, is determined by the kind of allele re- ceived from each parent and how the alleles interact with one another. Alleles are always located on the same spot (called a locus) on homologous chromosomes (Fig.

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