By W. Basir. Embry-Riddle Aeronautical University. 2018.

Cells in the substantia nigra in humans and primates differ from those in other species in containing granules of the lipoprotein pigment called neuromelanin buy sildigra 25 mg with amex. The melanin granules are free in the cytoplasm and give the SN a distinctive dark colour sildigra 120 mg without prescription. Cells in this nucleus can also have hyaline inclusion bodies discount 100mg sildigra amex, the Lewy bodies, which are not common normally but appear to increase dramatically in patients with Parkinsonism. Certainly they will require considerable biochemical back-up to maintain function in all their terminals. NEUROCHEMISTRY The biochemical pathways in the synthesis and metabolism of dopamine are shown in Fig. Although both phenylalanine and tyrosine are found in the brain it is tyrosine which is the starting point for NA and DA synthesis. It appears to be transported into the brain after synthesis from phenylalanine (phenylalanine hydroxylase) in the liver rather than from phenylalanine found in the brain. Despite the fact that the concentration of tyrosine in the brain is high (561075 M) very little body tyrosine (1%) is used for the synthesis of DA and NA. This is the rate-limiting step (K 561076 M) in DA synthesis, it requires molecular O and m 2 Fe2‡ as well as tetrahydropterine (BH-4) cofactor and is substrate-specific. It can be inhibited by a-methyl-p-tyrosine, which depletes the brain of both DA and NA and it is particularly important for the maintenance of DA synthesis. Since the levels of tyrosine are above the Km for tyrosine hydroxylase the enzyme is normally saturated and so it is not possible to increase DA levels by giving tyrosine. Dopa decarboxylase By contrast, the cytoplasmic decarboxylation of dopa to dopamine by the enzyme dopa decarboxylase is about 100 times more rapid (K :461074 M) than its synthesis and m indeed it is difficult to detect endogenous dopa in the CNS. This enzyme, which requires pyridoxal phosphate (vitamin B6) as co-factor, can decarboxylate other amino acids (e. Controls of synthesis It is possible to deplete the brain of both DA and NA by inhibiting tyrosine hydroxylase but while NA may be reduced independently by inhibiting dopamine b- hydroxylase, the enzyme that converts DA to NA, there is no way of specifically losing DA other than by destruction of its neurons (see below). In contrast, it is easier to augment DA than NA by giving the precursor dopa because of its rapid conversion to DA and the limit imposed on its further synthesis to NA by the restriction of dopamine b-hydroxylase to the vesicles of NA terminals. The activity of the rate-limiting enzyme tyrosine hydroxylase is controlled by the cytoplasmic concentration of DA (normal end-product inhibition), presynaptic dopamine autoreceptors (in addition to their effect on release) and impulse flow, which appears to increase the affinity of tyrosine hydroxylase for its tetrahydropteridine co-factor (see below). METABOLISM Just as the synthesis of DA and NA is similar so is their metabolism. They are both substrates for monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). In the brain MAO is found in, or attached to, the membrane of the intraneuronal mitochondria. Thus it is only able to deaminate DA which has been taken up into nerve endings and blockade of DA uptake leads to a marked reduction in the level of its deaminated metabolites and in particular DOPAC. The final metabolite, homovanillic 142 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION acid (HVA), is one that has been both deaminated and O-methylated so it must be assumed that most of any released amine is initially taken back up into the nerve where it is deaminated and then subsequently O-methylated (Fig. Certainly the brain contains much more DOPAC (the deaminated metabolite of DA) than the corresponding O-methylated derivative (3-methoxytyramine). It is possible, however, that the high levels of DOPAC, as found particularly in rat brain, partly reflect intraneuronal metabolism of unreleased DA and it is by no means certain that the metabolism of DA to HVA is always initially to DOPAC. Thus released DA that is not taken up into neurons is probably O-methylated initially by COMT. O-methylation It is generally accepted that COMT is an extracellular enzyme in the CNS that catalyses the transfer of methyl groups from S-adenylmethionine to the meta-hydroxy group of the catechol nucleus. Until recently the only inhibitors of this enzyme were pyragallol and catechol which were too toxic for clinical use. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like b-phenylethylamine, it is more affected by MAOB. Uptake The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity.

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For instance purchase 120mg sildigra with mastercard, whereas fibres emanating from the dorsal Raphe nucleus (DRN) are the major source of 5-HT terminals in the basal ganglia and cerebellum generic sildigra 25mg fast delivery, neurons in the median Raphe nucleus (MRN) provide the major input to the hippocampus and septum generic 50 mg sildigra with amex. There is also some evidence for morphological differences between DRN and MRN neurons which could impinge on their function. Thus, the terminals of neurons from the DRN are relatively fine, unmyelinated, branch extensively and seem to make no specialised synaptic contacts, suggesting en passant release of 5-HT (type I). The existence of co-transmitters, especially substance P, thyrotropin releasing hormone (TRH) and enkephalin, gives further options for functional specialisation of different neurons but, as yet, the distribution of these peptides within different nuclei has provided no specific clues as to how this might occur. In any case, species differences in the distribution of co-transmitters is a confounding factor. In short, although the 5-HT system seems to have a rather non-specific influence on overall brain function, in terms of the brain areas to which these neurons project, there is clearly much to be learned about possible functional and spatial specialisations of neurons projecting from different nuclei. SYNTHESIS The first step in the synthesis of 5-HT is hydroxylation of the essential amino acid, tryptophan, by the enzyme tryptophan hydroxylase (Fig. This enzyme has several features in common with tyrosine hydroxylase, which converts tyrosine to l-DOPA in 5-HYDROXYTRYPTAMINE 191 Figure 9. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydroxytryptophan is the rate- limiting step in the synthesis of 5-HT. The cytoplasmic enzyme, monoamine oxidase (MAOA), is ultimately responsible for the catabolism of 5-HT to 5-hydroxyindoleacetic acid the noradrenaline synthetic pathway. First, it has an absolute requirement for O2 and the reduced pterin co-factor, tetrahydrobiopterin. Second, hydroxylation of trypto- phan, like that of tyrosine, is the rate-limiting step for the whole pathway (reviewed by Boadle-Biber 1993) (see Chapter 8). However, unlike the synthesis of noradrenaline, the availability of the substrate, tryptophan, is a limiting factor in the synthesis of 5-HT. Indeed, the activated form of tryptophan hydroxylase has an extremely high Km for tryptophan (50 mM), which is much greater than the concentration of tryptophan in the brain (10±30 mM). This means that not only is it unlikely that this enzyme ever becomes saturated with its substrate but also that 5-HT synthesis can be driven by giving extra tryptophan. First, it predicts that a dietary deficiency of tryptophan could lead to depletion of the neuronal supply of releasable 5-HT. Indeed, this has been confirmed in humans to the extent that a tryptophan-free diet can cause a resurgence of depression in patients who were otherwise in remission (see Chapter 20). In contrast, a tryptophan-high diet increases synthesis and release of 5-HT. In fact, when given in combination with other drugs that augment 5-HT transmission (e. Transport of tryptophan across the blood±brain barrier and neuronal membranes relies on a specific carrier for large neutral amino acids (LNAAs). Thus, although an increase in the relative concentration of plasma tryptophan, either through dietary intake or its reduced metabolism in a diseased liver, increases its transport into the brain, other LNAAs (such as leucine, isoleucine or valine) can compete for the carrier. It is known that consumption of carbohydrates increases secretion of insulin which, in addition to its well-known glucostatic role, promotes uptake of LNAAs by peripheral tissues. However, it seems that tryptophan is less affected by insulin than the other LNAAs in this respect and so its relative concentration in the plasma increases, thereby increasing its transport into the brain (see Rouch, Nicolaidis and Orosco 1999). The resulting increase in synthesis and release of 5-HT is claimed to enhance mood. Although this scheme is rather controversial, it has been suggested as an explanation for the clinical improvement in some patients, suffering from depression or premenstrual tension, when they eat carbohydrates. It has also been suggested to underlie the carbohydrate-craving experienced by patients suffering from Seasonal Affective Disorder (Wurtman and Wurtman 1995). Not a great deal is known about factors that actually activate tryptophan hydroxylase. In particular, the relative contribution of tryptophan supply versus factors that specifically modify enzyme activity under normal dietary conditions is unknown. However, removal of end-product inhibition of tryptophan hydroxylase has been firmly ruled out. Also, it has been established that this enzyme is activated by electrical stimulation of brain slices, even in the absence of any change in tryptophan concentration, and so other mechanisms are clearly involved.

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