By N. Deckard. Ryokan College.
The latter is in turn converted by the enzyme succinic semialdehyde dehydrogenase (SSADH) into succinate buy cheap sildigra 25 mg,which re-enters the TCA cycle sildigra 50mg for sale. Other potential routes of GABA production have been described Ð involving deamination and decarboxylation reactions from putrescine 100mg sildigra for sale,spermine purchase 100mg sildigra visa,spermidine and ornithine Ð but the vast majority of GABA is generated by means of the GABA-shunt. GABA-T and SSADH are also present in the mitochondria of glial cells and are responsible for the degradation of GABA recovered from the extracellular space (see below). In this case the glutamate formed from the action of GABA-T is converted into glutamine by the cytosolic enzyme glutamine synthetase (GS). Glial glutamine serves as an important precursor for both neuronal glutamate and GABA. It is transported from glia into neurons where the mitochondrial enzyme phosphate-activated glutaminase (PAG) converts it back into glutamate. This neuronal glutamate can then be converted to GABA,either directly or following metabolism via the TCA cycle. The inter- conversion of glutamate and a-ketoglutarate is achieved by two further groups of AMINO ACIDS: INHIBITORY 227 Figure 11. Enzymes responsible for the syntheisis (GAD) and metabolism (GABA-T and SSADH) of GABA,and their relationship to the TCA cycle and the amino acids glutamate and glutamine. In glia,glutamate can be converted to glutamine by glutamine synthetase (GS). Dark-grey boxes denote enzymes present in both neurons and glia,light-grey boxes denote enzymes present only in neurons enzymes found in the mitochondria of both neurons and glia: the multi-enzyme complex glutamate dehydrogenase (GDH),and several aminotransferases (including aspartate and alanine aminotransferases) whose action is analogous to that of GABA-T. Regulation of GAD Of key importance in the synthesis of GABA is the short-term regulation of GAD activity. Increasing the availability of glutamate does not lead to an increase in the production of GABA,suggesting that GAD may normally be saturated with its substrate. GAD exists in two states; an inactive apoenzyme (apoGAD) lacking the co-factor and active 228 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION Figure 11. GABA produced by both GAD67 and GAD65 can be used as a neurotransmitter but GAD65 is preferentially associated with synaptic vesicles. Synaptically released GABA is recovered into neurons and glia by GABA transporters (not shown is the possible release of GABA by reversal of these transporters). Glutamine produced in glial cells is exported to neurons and converted to glutamate (after Soghomonian and Martin 1998) holoenzyme (holoGAD) complexed with PLP. During the synthetic process GAD can undergo cycles of interconversion between these states. Traditionally,two processes have been considered important with respect to the regulation of GAD. First,GABA may promote conversion of GAD from its active to its inactive state,and so cause feedback inhibition of GABA synthesis. Second,ATP appears to inhibit,while inorganic phosphate promotes,the reactivation of GAD by PLP. During periods of increased neuronal activity,when the consumption of ATP increases,a rise in the level of phosphate should stimulate the conversion of inactive to active GAD,thereby increasing GABA synthesis. More recently,it has been suggested that soluble and membrane-bound forms of GAD may be differentially regulated. The soluble form of GAD is activated by a phosphatase that causes dephosphorylation while the membrane-bound form is activated following phosphorylation by a vesicular protein kinase (Hsu et al. Active GAD (GAD-PLP) combines with glutamate (1) to form a complex (GAD-PLP±GLU). PMP dissociates from GAD (5) leaving inactive enzyme,which requires additional PLP to be reactivated (6),a process that is affected by ATP and inorganic phosphate Two isoforms of GAD In addition to the inactive and active states of GAD,there are two distinct forms of the enzyme. The two isoforms,GAD67 and GAD65,named for their respective molecular masses ($67 and $65 kDa),are encoded by separate,independently regulated genes, GAD1 and GAD2 (Erlander et al. GAD67 and GAD65 differ substantially in their amino-acid sequence,their interaction with PLP,their kinetic properties,and their regulation (Soghomonian and Martin 1998). Individual cells contain both forms of GAD but the ratio of the two differs among different neuronal populations. GAD65 is located preferentially in nerve terminals,both in the cytosol and as a membrane-bound form closely associated with synaptic vesicles into which the newly synthesised GABA is accumulated (see below).
The thickened length of the D2 receptor represents the amino-acid sequence missing in the short form of the receptor quality sildigra 50 mg. No attempt has been made to show differences in amino-acid sequencing or transmembrane topography DOPAMINE 147 (1) Those receptors are linked to different cellular actions and/or are located in different brain regions or parts of the neuron so as to produce different functional effects purchase sildigra 100 mg overnight delivery. To some extent these requirements are cyclic since the establishment of different functions (1) depends on the availability of appropriate drugs (2) buy 120 mg sildigra free shipping. There is no shortage of drugs cheap sildigra 100 mg free shipping, especially antagonists, but since the main difference in structure between DA receptors is intracellular, rather than at the binding or recognition site, very specific drugs may be hard to produce. Since receptors can be expressed in cell lines the affinity of drugs for the different receptors can, however, be established, as can their cellular actions. Detection of appropriate mRNA also makes it possible to map the distribution of the receptors. The main characteristics of the DA receptors are summarised below and in Table 7. D1 receptor family D1 Highest expression in human striatum and nucleus accumbens and olfactory tubercle but also some in cortex and hypothalamus. In the striatum 50% of medium sized striato-nigral neurons, which also express substance P, express them. Antagonists [ [ Clozapine Number High Low High Low Low Distribution Striatum [ [ Nuc. See Sibley and Monsma (1997), Sokoloff and Schwartz (1995) and Strange (1996). D5 Highest concentration in hippocampus and hypothalamus but much lower expression overall. Also linked to stimulation of adenylate cyclase but higher submicromolar affinity for DA (K1$200 nM). D2 receptor family D2 Mostly in striatum, nucleus accumbens and olfactory tubercle but also on neuron cell bodies in substantia nigra and ventral tegmentum where they are the auto- receptors for locally (dendritic) released DA. The loss of specific D2 antagonist binding in the striatum after lesions of the afferent nigro-striatal tract indicates their presynaptic autoreceptor role on terminals there. Other lesion studies have also established D2 receptors on other inputs such as the cortico striatal tract. As with D1 receptors some 50% of striatal medium-sized cells contain them but they are different neurons as they co-express enkephalin rather than substance P. The importance of this difference in the therapy of Parkinsonism is taken up later (Chapter 15). Although linked to inhibition of adenylate cyclase (and IP3 turnover) this is not their primary action. They increase K conductance (hyperpolarise neurons) but also inhibit Ca2 entry through voltage-sensitive channels, probably directly. When functioning as autoreceptors, these effects would also reduce DA release. The affinity for DA is slightly higher for the D2 (K1$400 nM) than for D1 receptors. No pharmacological differences have been established between the long or short forms of the D2 receptor. Mainly in limbic regions (nucleus accumbens and olfactory tubercle) but also in hypothalamus. Some in caudate and cortex and also expressed on DA neurons in substantia nigra, presumably as autoreceptors. No effect on adenylate cyclase but inhibits Ca2 entry (autoreceptor role). D4 Again very few in number compared with D2 but located in frontal cortex, mid- brain and amygdala. Comparison of the K1 values of various agonists and antagonists for the different receptors (Table 7. Some differences that have been exploited are the low affinity of raclopride for D4 receptors (compared with D2 and D3), the high affinity of clozapine and the benzamide derivative YM 43611 for the D4 (cf. Since only the latter is an agonist, however, their value in establishing the roles of the D3 and D4 receptors is limited, although the high affinity of clozapine for D4 receptors and their location in the frontal cortex has been considered, somewhat controversially, to be of significance in the aetiology and therapy of schizophrenia (see Chapter 17).
Digestive System © The McGraw−Hill Anatomy order sildigra 120mg with amex, Sixth Edition Body Companies 120mg sildigra for sale, 2001 648 Unit 6 Maintenance of the Body The motor and most of the sensory innervation to the Adventitia pharynx is via the pharyngeal plexus sildigra 100mg generic, situated chiefly on the middle constrictor muscle cheap sildigra 25mg. It is formed by the pharyngeal Tunica branches of the glossopharyngeal and vagus nerves, together with muscularis a deep sympathetic branch from the superior cervical ganglion. Submucosa The pharynx is served principally by ascending pharyngeal Mucosa arteries, which branch from the external carotid arteries. The pharynx is also served by small branches from the inferior thyroid Lumen arteries, which arise from the thyrocervical trunk. Describe the location of the parotid, submandibular, and sub- The lower esophageal (gastroesophageal) sphincter is a lingual ducts and state where they empty into the oral cavity. After food or fluid pass into the stomach, this sphincter constricts to prevent the stomach con- tents from regurgitating into the esophagus. There is a normal ESOPHAGUS AND STOMACH tendency for this to occur because the thoracic pressure is lower than the abdominal pressure as a result of the air-filled lungs. A bolus of food is passed from the esophagus to the stomach, where it is churned and mixed with gastric secretions. The chyme The lower esophageal sphincter is not a well-defined sphinc- thus produced is sent past the pyloric sphincter of the stomach to ter muscle comparable to others located elsewhere along the GI tract, and it does at times permit the acidic contents of the stom- the duodenum. This can create a burning sensation commonly called heartburn, although the heart is not involved. Certain Objective 10 Describe the location, gross structure, and mammals, such as rodents, have a true lower esophageal sphincter functions of the stomach. Objective 11 Describe the histological structure of the esophagus and stomach. List the cell types in the gastric mucosa, along with their secretory products. For descriptive purposes, deglutition The esophagus is that portion of the GI tract that connects the is divided into three stages. It is a collapsi- The first deglutitory stage is voluntary and follows mastica- ble tubular organ, approximately 25 cm (10 in. During this stage, the mouth is closed at the larynx and lying posterior to the trachea. A bolus is formed as The esophagus is located within the mediastinum of the the tongue is elevated against the transverse palatine folds thorax and passes through the diaphragm just above the opening (palatal rugae) of the hard palate (see fig. The upper third of the esophagus con- and are elicited by stimulation of sensory receptors located at the tains skeletal muscle; the middle third, a combination of skeletal opening of the oropharynx. Pressure of the tongue against the and smooth muscle; and the terminal portion, smooth muscle only. The soft palate and pendulant palatine uvula are elevated to esophagus: Gk. Digestive System © The McGraw−Hill Anatomy, Sixth Edition Body Companies, 2001 Chapter 18 Digestive System 649 Esophagus Esophagus Fundus Cardia Peristaltic contraction of muscularis layer of esophagus Lesser Greater curvature curvature Swallowed bolus entering stomach Duodenum Pylorus Body Stomach (a) FIGURE 18. Elevation of the larynx against the epiglottis seals the glottis so that food or fluid is less likely to enter the trachea. Sequential contraction of the constrictor mus- cles of the pharynx moves the bolus through the pharynx to the esophagus. The third stage, the entry and passage of food through the esophagus, is also involuntary. In the case of fluids, the en- tire process of deglutition takes place in slightly more than a sec- ond; for a typical bolus, the time frame is 5 to 8 seconds. Stomach (b) The stomach—the most distensible part of the GI tract—is lo- cated in the upper left abdominal quadrant, immediately below FIGURE 18. Typically J-shaped when empty, the stomach is stomach is a J-shaped organ. In A patient swallows radiopaque barium, which coats the lining of the stomach and duodenum. These structures and certain abnormalities the stomach, which serves as a “holding organ” for ingested food, may then show up in the radiograph. The stomach is divided into four regions: the cardia, fun- rect contact with the diaphragm.
As might be expected buy sildigra 25 mg mastercard, some DA side-effects such as dyskinesia and psychoses are worse order 120mg sildigra overnight delivery, but hypotension is less (no peripheral effects of DA) and vomiting is actually much reduced or abolished buy 100mg sildigra amex. This is because the chemoreceptor trigger zone of the vomiting centre while in the brain is on the blood side of the blood±brain barrier and will not be stimulated since no DA is formed peripherally (Fig cheap 120mg sildigra with amex. DA produces vomiting by acting on the chemo receptor trigger zone (CRTZ) of the vomiting centre (VC) outside, on the blood side, of the blood±brain barrier. When levodopa is given with an extracerebral dopa decarboxylase inhibitor like carbidopa it is not converted to DA peripherally and so there is no stimulation of the CRTZ. The emetic effect of a DA (D2) agonist can be prevented by a D2 antagonist like domperidone which acts only peripherally. This could also prevent the emetic effect of any DA formed peripherally from levodopa. Since neither carbidopa nor domperidone enter the CNS they do not modify the central effect of either levodopa or a DA agonist ExCDDI does reduce the peripheral metabolism of dopa in humans and increase the amount entering the brain in animals is shown in Fig. COMT inhibitors Levodopa is a better substrate for COMT than MAO and when given with an ExCDDI most of it is o-methylated to OMD (Fig. Recently COMT inhibitors have been developed which act either just peripherally (entacopone) or centrally as well DISEASES OF THE BASAL GANGLIA 309 Figure 15. Dopamine is not seen in either trace due to its rapid metabolism to DOPAC and HVA. Peaks for both these metabolites are seen in (i) but they are much reduced in (ii) indicating that in the presence of benserazide very little DA had been formed peripherally. The OMD peak is much greater after benserazide, which again indicates that dopa has been o-methylated (by COMT) rather than decarboxylated. Both have been tried clinically and shown to prolong the plasma half- life and effect of dopa (ExCDDI). Long-term effects After some 5 years of treatment, most patients show (1) Abnormal involuntary movements (AIMs), manifest mainly as dyskinesias at the peak plasma level of dopa. A patient may be walking fairly well but then become suddenly akinetic and fixed before quickly moving again. These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. As the disease progresses there will presumably be a further loss in the ability of striatal neurons to synthesise DA whether from endogenous or exogenous dopa but the occurrence of dyskinesias suggests that enough DA can somehow still be formed. In view of the complexity of the striatal output pathways and the critical role of DA in controlling the balance between them it is perhaps not surprising that sudden swings in motor function can occur especially with a drug like levodopa that affects both outputs (see below). Attention has been given to the possibility that some of the above motor effects may arise from a metabolite of levodopa. The prime suspect is OMD which has a half-life of some 20 hours and reaches plasma concentrations three- to fourfold those of dopa. Suggestions that it may compete with dopa for entry across the blood±brain barrier or act as a partial agonist (effective antagonist) have not been substantiated experi- mentally although it does reduce DA release from rat striatal slices. Also if free radical production through deamination of DA is neurotoxic (see below) then this would be increased by levodopa. Despite all these problems, levodopa improves the life of the PD patient, effectively slows progession of the disease and prolongs life. They do not have to be converted to DA, they can be designed to be long- acting, cross the blood±brain barrier and act on specific DA receptors. Despite the fact that in quantitative studies of motor performance they often appear to produce more benefit than levodopa and are less likely to cause dyskinesia and ON± OFF fluctations, patients tend to prefer levodopa. Possibly unless DA function is DISEASES OF THE BASAL GANGLIA 311 Figure 15. The structure of DA is shown for comparison and its configuration emphasised in the agonist structure where appropriate pushed towards the extreme of causing dyskinesia, as with levodopa, there is inadequate release from akinesia. With most DA agonists there are the other expected signs of increased DA activity such as hallucinations, psychosis and hypotension which can be worse than with levodopa. Fortunately vomiting can be countered by giving the DA antagonist domperidone.