Neurotransmitters and Hormones

Numerous reports of altered neurotransmitter and hormone functions which have been associated with the affective disorders are reviewed by Levell [142]. It was originally proposed that one or more of the neurotransmitter amines in the brain (norepinephrine, dopamine, serotonin) may be functionally elevated in manic patients and reduced in depressed patients [143]. For instance, an increase in the production of dopamine, observed in a number of case reports, is thought to be the cause of the switch into the manic phase in bipolar patients. For example, Bunney et al. reported an increase in the level of homovanillic acid (HVA), a 

Dougherty, Ts the brain ready for physical organic chemistry , J. Phys. Org. Chem., 1998, 11, 334-340. 

To illustrate the supramolecular biological role of such molecular species we will look at the mode of action of acetylcholine (ACh, 2.8) in particular since this example highlights the profound effect that the non-covalent binding of a small molecular guest may have on a biological system. 

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Obviously, regulation of food intake depends on many neurotransmitters and hormones but this final section will outline the role played by central 5-HT transmission in this process. It had been the belief for some time that increased 5-HT transmission in the brain reduces food intake (Blundell 1977) and this certainly explains the satiety in rats that follows infusion of 5-HT into the paraventricular nucleus (PVN) of the hypothalamus. However, recent studies using microdialysis have found that 5-HT efflux in the lateral hypothalamus is itself increased by food intake, suggesting the existence of a feedback control system. In fact, because the increase in 5-HT efflux is greater in genetically obese rats than in their lean counterparts, it has been proposed that there is a deficiency in the 5-HT inhibition of food intake in obesity. 

Neurons can be excitatory, inhibitory or modulatory in their effect and motor, sensory or secretory in their function [6], They can be influenced by a large repertoire of neurotransmitters and hormones (see Ch. 10). This enormous repertoire of functions, associated with different... 

A variety of methods have been developed to study exocytosis. Neurotransmitter and hormone release can be measured by the electrical effects of released neurotransmitter or hormone on postsynaptic membrane receptors, such as the neuromuscular junction (NMJ see below), and directly by biochemical assay. Another direct measure of exocytosis is the increase in membrane area due to the incorporation of the secretory granule or vesicle membrane into the plasma membrane. This can be measured by increases in membrane capacitance (Cm). Cm is directly proportional to membrane area and is defined as Cm = QAJV, where Cm is the membrane capacitance in farads (F), Q is the charge across the membrane in coulombs (C), V is voltage (V) and Am is the area of the plasma membrane (cm2). The specific capacitance, Q/V, is the amount of charge that must be deposited across 1 cm2 of membrane to change the potential by IV. The specific capacitance, mainly determined by the thickness and dielectric constant of the phospholipid bilayer membrane, is approximately 1 pF/cm2 for intracellular organelles and the plasma membrane. Therefore, the increase in plasma membrane area due to exocytosis is proportional to the increase in Cm. 

There are also many neurotransmitter and hormone receptors that contribute to the fine control of cAMP formation by inhibition of adenylyl cyclase. The action of inhibitory receptors is mediated by several different forms of the Gai family, specifically the Gail, Gai2, Gai3, Gao and Goa subtypes. The Ga subunits of these isoforms can inhibit the catalytic activity of adenylyl cyclase when the enzyme is activated by either Gas or forskolin. The inhibition of catalytic activity does not occur via competition with Gas but appears to occur by an interaction at a symmetric site on the AC molecule. Gai-mediated inhibition of adenylyl cyclase is most dramatic for AC5 and AC6. A few other forms of adenylyl cyclase, most notably AC1, can be inhibited by Gao but this effect is not as potent as the inhibition of AC5 and AC6 by Gai isoforms. The GTPase activity of Gai family members can be accelerated by a large family of RGS proteins (see Chapter 19). 

How do a wide variety of neurotransmitters and hormones produce tissue- and cell-specific biological responses, if many such responses are mediated by the same intracellular messengers, cAMP and cAMP-depen-dent protein kinase Specificity is achieved at two levels at the level of tissue-specific receptors for the neurotransmitter or hormone and at the level of tissue-specific substrate proteins for the protein kinase. Only tissues that possess specific receptors will respond to a certain neurotransmitter or hormone. Moreover, since all cells contain very similar catalytic subunits of protein kinase A (see Ch. 23), the nature of the proteins that are phosphor-ylated in a given tissue depends on the types and amounts of proteins expressed in that tissue and on their accessibility to the protein kinase. 

The effects of Li+ upon this system have been reviewed in depth by Mork [131]. Animal studies originally demonstrated that Li+ inhibits cAMP formation catalyzed by adenylate cyclase in a dose-dependent manner [132]. The level of cAMP in the urine of manic-depressive patients changes with mental state, being abnormally elevated during the switch period between depression and mania it is proposed that Li+ s inhibitory effect upon adenylate cyclase activity may correct this abnormality. Subsequent research, in accord with the initial experiments, have shown that Li+ s interference with this second messenger system involves more than one inhibitory action. At therapeutic levels, Li+ inhibits cAMP accumulation induced by many neurotransmitters and hormones, both in... 

Whatever the mechanism of action of Li+ in the treatment of bipolar affective disorder turns out to be, there is no doubt that the functions of one or more of the neurotransmitters and hormones are involved to some extent. Much of the published data on the effects of Li+ on these systems is equivocal or even contradictory, in many cases reflecting differences in the experimental procedures, in particular the levels of Li+ employed. Often, where it has been looked for, there are differences observed between the acute and chronic effects of Li+. Therefore, the therapeutic relevance of many of these Li+-induced effects is difficult to assess. 

The mechanisms of most drugs involve binding of the drug to a receptor. A receptor may be any macromolecular target, but the most common receptors are proteins. These include membrane proteins, enzymes, transporters, and structural elements. Some of the main receptors of interest for psychopharmacology are receptors for neurotransmitters and hormones, which show a high degree of selectivity. 

Receptors can mediate the action of endogenous signalling compounds and may therefore be viewed as regulatory proteins. Such receptors are the physiological targets for neurotransmitters and hormones. Other types of receptors include enzyme proteins, transport proteins and structural proteins. For example, statins inhibit an enzyme catalysing the synthesis of cholesterol and loop diuretics inhibit an enzyme that facilitates the re-uptake of salt in primary urine. 

B. An antagonist binds to a receptor and prevents the action of an agonist. Choice A is wrong because this combination does initiate a signal transduction process. C and D are incorrect because both neurotransmitters and hormones work through their appropriate receptor to initiate signal transduction. 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

The secretion of anterior pituitary hormones is controlled in part by hypothalamic regulatory factors that are stored in the hypothalamus and are released into the adenohypophyseal portal vasculature. Hypothalamic regulatory factors so far identified are peptides with the exception of dopamine. Secretion of anterior pituitary hormones is also controlled by factors produced more distally that circulate in the blood. Predominant control of hormone production may be relatively simple, as with thyroid-stimulating hormone (TSH), the production of which is primarily stimulated by thyrotropin-releasing hormone (TRH) and inhibited by thyroid hormones, or it may be complex, as with prolactin, the production of which is affected by many neurotransmitters and hormones. 

Calcium is the principal extracellular electrolyte regulated by PTH, calcitonin, and D3. Extracellular calcium is a critical component of signal transduction across the plasma membrane, which regulates a wide spectrum of physiological events including muscle contraction, secretion of neurotransmitters and hormones, and the ac-... 

Mechanism of Action An electrolyte that is essential for the function and integrity of the nervous, muscular, and skeletal systems. Calcium plays an important role in normal cardiac and renal function, respiration, blood coagulation, and cell membrane and capillary permeability. It helps regulate the release and storage of neurotransmitters and hormones, and it neutralizes or reduces gastric acid (increase pH). Calcium acetate combines with dietary phosphate to form insoluble calcium phosphate. Therapeutic Effect Replaces calcium in deficiency states controls hyperphosphatemia in end-stage renal disease. 

People suffering from PTSD frequently have abnormal levels of the hormones that are involved in the body s response to stress. Studies have shown that baseline cortisol levels in people with PTSD are lower than normal, and epinephrine and norepinephrine levels are higher than normal. However, it is not known whether these differences in hormones and neurotransmitters involved in the bod/s stress response precede or follow the development of the disorder. It is important to note that the neurotransmitter and hormone changes seen with PTSD are separate from, and actually opposite to, those seen in major depression. In major depression, cortisol levels are elevated and epinephrine and norepinephrine levels are low. The distinctive profile associated with PTSD is also seen in individuals who have both PTSD and depression. One hypothesis is that people who cannot mount a robust stress... 

Peptides function as neurotransmitters and hormones and thus are good starting materials when designing bioactive molecules. 

FIGURE 2—2. A side view of a receptor with seven transmembrane regions is shown here. This is a common structure of many receptors for neurotransmitters and hormones. That is, the string of amino acids goes in and out of the cell several times to create three portions of the receptor first, that part that is outside of the cell (called the extracellular portion) second, the part that is inside the receptor that is inside the cell (called the intracellular portion and finally, the part that traverses the membrane several times (called the transmembrane portion). Throughout this text, this receptor will be represented in a simplified schematic manner with the icon shown in the small box. 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

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