Neurotransmitters
J.R. Cooper, in International Encyclopedia of the Social & Behavioral Sciences, 2001
2 Biogenic Amines
Four neurotransmitters come under the chemical classification of biogenic amines. These are epinephrine, norepinephrine, dopamine, and serotonin. Although epinephrine is the transmitter in frogs, in mammals its role has been supplanted by norepinephrine. Epinephrine's function in the mammalian brain is still unclear and may be limited to a hormonal role.
Starting with tyrosine, the catecholamines (norepinephrine and dopamine) are synthesized in a cascade of reactions beginning with the rate-limiting enzyme, tyrosine hydroxylase. Figure 2 depicts the enzymes and cofactors involved. The catecholamines are catabolized by two enzymatic pathways (Fig. 3) involving monamine oxidase, a neuronal mitochondrial enzyme, and catechol-o-methyltransferase, a cytoplasmic enzyme, found primarily in the kidney and the liver. However, as noted earlier, when norepinephrine and dopamine are released into the synapse, their activity is terminated by reuptake into the presynaptic terminal rather than by enzymatic catabolism. The reuptake is inhibited by a number of antidepressant drugs.
Noradrenergic neurons arise from the locus coeruleus, the lateral tegmental system, and a dorsal medullary group and innervate virtually all areas of the brain and spinal cord. Central effects of noradrenaline stimulation are not clear but appear to involve behavioral attention and reactivity.
Peripherally where noradrenaline is released from postganglionic sympathetic neurons of the autonomic nervous system, the major effects are to regulate blood pressure, relax bronchi, and relieve nasal congestion. These effects are mediated by the major receptors, α and β, each again with multiple subtypes.
At one time dopamine was thought to be just an intermediate in the conversion of tyrosine to noradrenaline. It is now clear, however, that dopamine is a major player in the CNS with its implication in Parkinson's disease and in schizophrenia. Dopamine cells originate in the substantia nigra, ventral tegmental area, caudal thalamus, periventricular hypothalamus, and olfactory bulb. Dopaminergic terminals are found in the basal ganglia, the nucleus acumbens, the olfactory tubercle, the amygdala, and the frontal cortex. The nigrostriatal pathway is particularly important since its degeneration is involved in Parkinson's disease. Initially, dopamine receptors were classified as D1 or D2. Currently the subtypes consist of D1 through D5 with the possibility of a D6. All the receptors are coupled to G proteins as their second messenger. Arising from the observation that a correlation existed between therapeutic doses of antipsychotic drugs and inhibition of binding of dopamine receptor antagonists, the D2 receptor has been fingered in the pathophysiology of schizophrenia. The atypical neuroleptic drug clozapine, however, exhibits a greater affinity for the D4 receptor, dopaminergic transmission in the nucleus accumbens, involving both D1 and D2 receptors, is believed to be involved in the reward activity of abused drugs such as cocaine. The catabolism of dopamine is shown in Fig. 4.
The last of the biogenic amine neurotransmitters to be discussed is serotonin (5-hydroxytryptamine). Its synthesis and its catabolism are depicted in Figs. 5 and 6. In addition to its presence in the CNS, serotonin is found in the GI tract and in blood platelets. It is also localized in the pineal gland where it serves as a precursor to the hormone melatonin. Serotinergic neurons innervate the limbic system, the neostriatum, cerebral and cerebellar cortex and the thalamus. Currently, 18 serotonin receptor subtypes have been identified. Most are G-protein linked except for the 5-HT3 receptor which is ligand gated. Hallucinogen drugs have been shown to act on the 5-HT2A receptors. Serotonin receptor antagonists that are relatively specific have been used to treat migraine headaches, body-weight regulation and obsessive–compulsive disorders.
Decarboxylation of the amino acid histidine results in the formation of histamine, a still questionable neurotransmitter. This amine does not qualify as a transmitter according to the rigid definitions outlined earlier, since no evidence exists for either its release on stimulation of a neuronal tract, nor is there a rapid reuptake mechanism or enzymatic catabolism to terminate its activity. Histaminergic neurons are located almost exclusively in the ventral posterior hypothalamus and project throughout the entire CNS. Three histamine receptors have been described, H1, H2 and H3. Antagonists of H1 are the well-known antihistamine drugs which exhibit a sedative action. H2 antagonists are used to block gastric acid secretion. H3 receptors are autoreceptors which, when activated, inhibit the release of histamine.