Basic Neuropharmacology
Neuropharmacology is the pharmacology of the nervous system. The nervous system coordinates cellular activity, and the neuron is its basic component. The principal mechanism by which neurons communicate with one another is through the release of chemical mediators known as neurotransmitters. A chemical substance must possess several qualities before it can be classified as a neurotransmitter (Table 3-1).
A neurotransmitter has to be differentiated from another chemical messenger, namely a hormone. Hormones are secreted into the bloodstream, exert their effects throughout the body, and have a relatively long half-life. In contrast, neurotransmitters usually communicate point to point, are released by one neuron onto another neuron, and have a short half-life.
In order for a neuron to act swiftly and repeatedly it needs a synthetic mechanism to constantly replenish the neurotransmitters it releases. The synthetic apparatus is located in the cell body. After synthesis, neurotransmitters are transported down the axon to pre-synaptic nerve terminals where they are stored in synaptic vesicles. The presynaptic terminal is in proximity to a specialized area of the adjacent neuron referred to as the postsynaptic site. Information from the released neurotransmitter is conveyed to the adjacent neurons via the postsynaptic site. For many neurotransmitters the presynaptic nerve terminal has a mechanism that rapidly replenishes released transmitter (a process referred to as recapture ). The released neurotransmitter (or the hydrolytic product that can be reused to synthesize new transmitter substance) is taken back into the presynaptic vesicles by an active—and, in the case of some neurotransmitters, a specific—reuptake process (Table 3-1)).
(Table 3-1)) Synaptic neurotransmission sites. (1) Cell body where synthesis of the neurotransmitter occurs; (2) microtubules, involved in the transport of macromolecules between the cell body and the distal nerve terminal; (3) transport site for uptake of the precursor or neurotransmitter into presynaptic storage vesicles; (4) pre-synaptic storage vesicles; (5) postsynaptic neurotransmitter receptors; (6) site of transporters for the reuptake of the released neurotransmitter into the presynaptic vesicle; (7) presynaptic neurotransmitter receptors.
The list of chemical substances classified as neurotransmitters is ever-growing. In the 1950s and 1960s norepinephrine, serotonin, dopamine, and acetylcholine were thought to be the principal neurotransmitters. Subsequent studies added the amino acids gamma amino butyric acid (GABA), glycine, glutamic acid, and aspartic acid. Several peptides satisfy criteria for classification as neurotransmitters. Furthermore, the presynaptic vesicles at the nerve terminals can contain more than one neurotransmitter, so that more than one transmitter substance is released following depolarization of the nerve ending.
Catecholamines
The catecholamines are molecules that contain a 3,4-dihydroxyphenyl nucleus. Norepinephrine and dopamine are neurotransmitters, whereas epinephrine, which is also a catecholamine, is classified as a hormone (Figure 3-2). Nevertheless, epinephrine is present in the CNS, and it may have a role as a neurotransmitter. Although the presence in systemic tissues of epinephrine and norepinephrine had long been known, it was not until 1948 that they were found in mammalian sympathetic nervous tissue. About the same time, researchers discovered dopamine, a catecholamine lacking a ß-hydroxy group on the side chain.
Figure 3–2. Structures of catecholamines.
Catecholamine Metabolism
The biosynthetic pathway for the catecholamines proceeds as follows: tyrosine-> dopa-> dopamine-> norepinephrine-> epinephrine (Figure 3-3). Tyrosine hydroxylase, which forms dopa from tyrosine, is the rate-limiting step in the synthesis of norepinephrine. The metabolism of dopamine and norepinephrine is shown in Figure 3-4 and 3-5.
Although the main dietary precursor of the catecholamines is tyrosine, dietary phenylalanine can be converted to tyrosine via the enzyme phenylalanine hydroxylase. The conversion of tyrosine to dopa is catalyzed by the enzyme tyrosine hydroxylase, which can also hydroxylate phenylalanine. Consequently, the conversion of phenylalanine to tyrosine occurs not only in the adrenal medulla and sympathetically innervated tissues but also in the brain. Tyrosine hydroxylase is an oxygenase that catalyzes the conversion of tyrosine to dopa, the initial step in the biosynthesis of norepinephrine. Tyrosine hydroxylase requires tetrahydropteridine as a cofactor. Because tyrosine hydroxylation is the rate-limiting step in the biosynthesis of catecholamines, it is the step to block if one wishes to halt the synthesis of norepinephrine. Tyrosine hydroxylase can be inhibited by a number of chemicals. Substrate analogues such as L
-methyl-p-tyrosine inhibit the enzyme in vitro, and in vivo they decrease the endogenous levels of norepinephrine by competing with tyrosine. There is also a feedback regulation of catecholamine biosynthesis so that various catecholamines, such as dopa, dopamine, norepinephrine, and epinephrine, inhibit tyrosine hydroxylase by interacting with the cofactor tetrahydropteridine. The relationship between the biosynthetic pathways of catecholamine and serotonin is demonstrated by the fact that certain tryptophan derivatives can inhibit tyrosine hydroxylase. One of the most potent inhibitors of tyrosine hydroxylase is -methyl-5-hydroxytryptophan.
The next enzyme in the biosynthetic pathway is aromatic-L-amino acid decarboxylase, otherwise known as dopa decarboxylase, which was discovered in 1938. This enzyme is not specific for the decarboxylation of dopa. It also decarboxylates aromatic-L -amino acids such as 5-hydroxytryptophan, phenylalanine, tryptophan, and tyrosine. Dopa decarboxylase is widely distributed in a number of mammalian organs. Pyridoxal-5-phosphate activates dopa decarboxylase and is tightly bound to the enzyme. Dopa, dopamine, and norepinephrine inhibit dopa decarboxylase by forming a Schiff’s base with pyridoxal-5-phosphate. Several substances inhibit dopa decarboxylase (eg, -methyl dopa, -methyl-5-hydroxytryptophan, and N -m-hydroxylbenzyl-N-methyl hydrazine).
Dopamineß-hydroxylase (DBH) is the final enzyme in the synthesis of norepinephrine. It catalyzes the conversion of dopamine to norepinephrine. DBH hydroxylates dopamine on the ß carbon to form norepinephrine. The enzyme has a requirement for Cu++, and ascorbic acid is necessary for the reoxidation of the Cu++. Although it is referred to as dopamine-ß-hydroxylase, the enzyme is not completely specific as it can also hydroxylate, on the ß carbon, a number of phenylethylamines (eg, tyramine-> norsynephrine [octopamine]; amphetamine-> nore!phedrine; epinine-> epinephrine; mescaline-> ß hydroxy mescaline). A number of inhibitors have been found that bind the copper of DBH (eg, disulfiram, tropolone, aromatic and alkyl thioureas, fuseric acid).
