Catecholamines as neurotransmitters

The postsynaptic receptors on any given neuron receive information from transmitters released from another neuron. Typically, postsynaptic receptors are located on dendrites or cell bodies of neurons, but may also occur on axons or nerve terminals in the latter case, an axoaxonic synaptic relationship may cause increases or decreases in transmitter release. In contrast, autoreceptors are found on certain neurons and respond to transmitter molecules released from the same neuron. Autoreceptors may be widely distributed on the surface of the neuron. At the nerve terminal, they respond to transmitter molecules released into the synaptic cleft on the cell body, they may respond to transmitter molecules released by dendrites. Functionally, most autoreceptors appear to decrease further transmitter release in a kind of negative feedback loop. Autoreceptors have been identified for all the catecholamines, as well as for several other neurotransmitters. a2-adrenergic receptors are often found on noradrenergic nerve terminals of postganglionic sympathetic nerves, as well as on noradrenergic neurons in the CNS [36], and activation of these receptors decreases further norepinephrine release. Dopamine autoreceptors,... 

Histamine, serotonin, melatonin, and the catecholamines dopa, dopamine, norepinephrine, and epinephrine are known as "biogenic amines."They are produced from amino acids by decarboxylation and usually act not only as hormones, but also as neurotransmitters. 

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

Catecholamines produced in the brain and in other neural tissues function as neurotransmitters, but epinephrine and norepinephrine are also hormones, synthesized and secreted by the adrenal glands. Like the peptide hormones, catecholamines are highly concentrated within secretory vesicles and released by exocytosis, and they act through surface receptors to generate intracellular second messengers. They mediate a wide variety of physiological responses to acute stress (see Table 23-6). 

Dopamine, norepinephrine, and epinephrine (adrenalin) are biologically active amines that are collectively termed catecholamines. Dopamine and norepinephrine function as neurotransmitters in the brain and the autonomic nervous system. Norepinephrine and epinephrine are also synthesized in the adrenal medulla. 

A combination of decarboxylation and hydroxyla-tion of the ring of tyrosine produces derivatives of o-dihydroxybenzene (catechol), which play important roles as neurotransmitters and are also precursors to melanin, the black pigment of skin and hair. Catecholamines may be formed by decarboxylation of tyrosine into tyramine (step e, Fig. 25-5) and subsequent oxidation. However, the quantitatively more important route is hydroxylation by the reduced pterin-dependent tyrosine hydroxylase (Chapter 18) to 3,4-dihydroxyphenylalanine, better known as dopa. The latter is decarboxylated to dopamine.1313 Hydroxylation of dopamine by an ascorbic acid and... 

Specifically, the deflciency of certain enzymes of tetrahydrobiopterin biosynthesis (GTP cyclohydrolase 1, pymvoyltetrahy-drobiopterin synthase. Fig. 3) result in severe neurological and developmental deflcits designated as atypical phenylketonuria caused by the ensuing deflciency in catecholamine type neurotransmitter biosynthesis. The condition can be treated with some success by the oral application of synthetic tetrahydrobiopterin in large amounts. More recently, tetrahydrobiopterin therapy has also been advocated for certain patients with classic phenylketonuria that results from mutations of phenylalanine hydroxylase... 

Norepinephrine and epinephrine are hormones in the class called catechoiami nes. The catecholamines are synthesized and stored in the adrenal gland. With exercise, nerve impulses stimulate the adrenal gland to release the hormones into the bloodstream. Elevated levels of the plasma catecholamines, in turn, induce the contraction or dilation of specific arteries, and the synthesis of cAMF in various cells. Norepinephrine and epinephrine are stored in and released by nerve endings and, for this reason, these hormones are also classed as neurotransmitters. The catecholamine biosynthetic pathway begins with tyrosine (Figure 9.85). 

Among the most important neurotransmitters are acetylcholine (ACh), amino acids and their derivatives, and certain polypeptides known as neuropeptides. In fact, the mammalian nervous system is said to employ over 30 different substances as neurotransmitters. For the record, among the amino acids and their derivatives (called biogenic amines) are many that are also hormonally active in the bloodstream, and include the catecholamines dopamine, norepinephrine, and epinephrine, as derived sequentially from tyrosine, whereas y-aminobutyric acid (GABA), histamine, and serotonin are derived from glutamate, histidine, and tryptophan, respectively. The subject interfaces with the biochemical aspects of psychology, which may also be referred to as the mind-body connection, or psychosomatics. 

FIGURE 7-41 Structures of several small molecules that function as neurotransmitters. Except for acetylcholine, all these are amino acids (glycine and glutamate) or derived from the indicated amino acids. The three transmitters synthesized from tyrosine, which contain the catechol moiety (blue highlight), are referred to as catecholamines. 

Catecholamines. The peripheral aspects of NE and EP as neurotransmitters were considered in Chapter 9. NE exists at significant levels in the hypothalamus and in lesser amounts in the medulla oblongata, midbrain areas, and the pons. EP, the adrenal hormone, may possibly have some central transmitter functions. DA, however, has major involvement in central mechanisms and will be considered further here. 

Glycine and glutamate are amino acids that serve directly as neurotransmitters are. y-Aminobutyric acid (GABA), the decarboxylation product of glutamate, is also a neurotransmitter. Amino acid metabolites that function in neurotransmission include histamine (from histidine), serotonin (from tryptophan), and catecholamines (epinephrine, dopamine, and norepinephrine), which are derived from tyrosine. 

Distinctions among these classes of regulators are somewhat indefinite. Catecholamines, such as epinephrine and norepinephrine, function both as neurotransmitters and as hormones, depending upon their sites of synthesis and release. 

Epinephrine and norepinephrine are catecholamines which, when released from presynaptic nerve endings, function as neurotransmitters (see here). When released from adrenal medulla in response to low blood glucose levels, epinephrine interacts with second-messenger systems in many tissues, with varied effects. In muscle, epinephrine activates adenylate cyclase, with concomitant activation of glycogenolysis and inhibition of glycogen synthesis. 

Amino Acids and Their Metabolites as Neurotransmitters and Biological Regulators Biosynthesis of Serotonin and Catecholamines (Diagram, Figure 21.32)... 

Catecholamines (dopamine, norepinephrine), opioid peptides, and serotonin act as neurotransmitters in nonspecific or diffuse neuronal systems. Glutamate is the primary excitatory transmitter in hierarchical neuronal systems. The answer is (B). 

Acetylcholine seems the most widely distributed of the neurotransmitters in the c.n.s., and both muscarinic and nicotinic receptors have been recognized, the former being the more common (Kuhar, 1978). Three catecholamines (epinephrine, norepinephrine, and dopamine) also play important roles as neurotransmitters, each with its own system of nerves to operate on (Moore and Bloom, 1979). 5-Hydroxytryptamine 7.49) is an important transmitter in the midbrain and pons. 

Most neurons communicate with one another by the secretion of chemical substances known as neurotransmitters. Neurotransmission occurs in a region known as the synapse which constitutes the input of one neuron and the output of the neuron secreting the transmitter. Since neurons form synapses throughout the brain, one would expect that the cellular heterogeneity would also be reflected in a chemical heterogeneity of neurotransmitter concentrations within the brain. This hypothesis can be tested for catecholamine neurotransmitters because carbon fiber microelectrodes Implanted in the brain can detect them voltammetrlcally. 

Amino acids are involved in many metabolic processes and m protein synthesis. In the central nervous system, they also function as neurotransmitters or neuromodulators (Davidson, 1976 Corradetti et al., 1983 Fonnum, 1981, 1984). Numerous studies have demonstrated the excitatory effects of aspartate and glutamate (Watkins and Evans, 1981) the inhibitory effects of glycine, y-aminobutyric acid (GABA), and taurine (Schaffer et al., 1981 Lloyd et al., 1983 Roberts, 1984), and the precursor roles of tryptophan in serotonin synthesis and of tyrosine and phenylalanine in the biosyntheses of catecholamines (Sved, 1983). It is not surprising, therefore, to see an ever-increasing interest in amino acid analysis in biological samples. 

Catecholamines and their metabolites The catecholamines, adrenaline, noradrenaline, and dopamine are essential components of the central nervous system acting as neurotransmitters both within the brain and at peripheral nerves. All are synthesized in the adrenal medulla from phenylalanine or tyrosine and are metabolized by a mixture of enzymatic side chain oxidation and methylation of the hydroxy groups on the ring. If the metabolism is complete, adrenaline and noradrenaline are degraded to 4-hydroxy-3-methoxy mandelic acid (HMMA, commonly called vanillylmandelic acid - VMA), while dopamine is broken down to homovanillic acid (HVA). Urinary excretion of these metabolites and their conjugates is the major route of elimination of catecholamines from the body, although small amounts are excreted unchanged as the free catecholamines. 

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