NEUROACTIVE CHEMICALS

Neurons in the CNS produce a large number of special molecules which function as neurotransmitters or are suspected to do so, including acetylcholine (ACh), norepinephrine (NE), dopamine (DA), y-aminobutyric acid (GABA), aspartic acid, glutamic acid, glycine, and substance P. CNS neurons also syn­thesize a number of neuropeptides which perform quite specific endocrine roles. We will take a closer look at these neuroactive chemicals now.

Acetylcholine

Acetylcholine has long been recognized as an important neurotransmitter. It's released by preganglionic sympathetic and parasympathetic nerve fiber termi­nals as well as postganglionic parasympathetic and certain select sympathetic fibers. It is also the only recognized neurotransmitter at the skeletal muscle neuromuscular junction. Unfortunately we don't have nearly as complete a pic­ture of the distribution of cholinergic neurons in the CNS. There appear to be cholinergic fibers associated with the arousal or activating systems of the brain which project from the midbrain reticular formation, hypothalamus striatum, and septum to the neocortex. ACh and the enzymes necessary for its synthesis are also found in the hippocampus, corpus striatum, and retina.

Acetylcholine is formed by the reaction of choline with acetyl coenzyme A (acetyl CoA) in the presence of the enzyme choline acetyltransferase (CAT). Since neurons can't synthesize choline, the ultimate source of choline for ACh synthesis is the choline of the plasma. Acetyl CoA is synthesized within presynaptic cytoplasm by the A TP-energized reaction of acetate with CoA. Once ACH has been synaptically released and has produced its postsynaptic effects on membrane permeability, it is hydrolyzed within microseconds by the enzyme acetylcholinesterase (AChE). Interestingly enough, while negligible amounts of ACh are reabsorbed by presynaptic terminals in the peripheral ner­vous system (hydrolysis by AChE being overwhelmingly dominant), its reuptake by the terminals in brain is considerable. Nevertheless, its failure to be resequestered into synaptic vesicles leaves the significance of this process in doubt.

Acetate + CoA + ATP ~ acetyl CoA + AMP + 2Pi

Catecholamines

The catecholamine neurotransmitters are norepinephrine (NE) and dopamine (DA). The synthesis of both of these amines proceeds from the amino acid tyrosine (Fig. 17-5). Tyrosine is converted to 3,4-dihydroxyphenylalanine (dopa) by the enzyme tyrosine hydroxylase. Subsequent decarboxylation by dopa decarboxylase converts dopa to 3,4-dihydroxyphenylethylamine (dopa­mine). This is as far as the synthesis proceeds in dopaminergic neurons. In norepinephrinergic neurons, an additional step converts dopamine to norepi­nephrine by action of the enzyme dopamine ,B-hydroxylase.

The enzymatic degradation of the two catecholamines is illustrated in Fig. 17-6. Catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO) produce inactive products which have little effect on receptor sites. MAO catalyzes the oxidative deamination of norepinephrine to 3,4-dihydrox­ymandelic acid and dopamine to 3,4-dihydroxyphenylacetic acid. These prod­ucts are then methylated by COMT to 3-methoxy-4-hydroxymandelic acid and homovanillic acid, respectively. Alternatively, norepinephrine can first be methylated to normetanephrine and then deaminated to 3-methoxy-4-hydroxymandelic acid.

Distribution of Norepinephrinergic Fibers

The distribution of norepi­nephrinergic fibers in the peripheral nervous system is limited to the majority of postganglionic sympathetic neurons. Norepinephrine-releasing neurons in the central nervous system have their cell bodies located in the midbrain, pons, and medulla, primarily in the reticular formation. Two norepinephrine systems are often described in the mammalian brain: the locus ceruleus system and the lateral tegmental system. The cell bodies of the former are located in the locus ceruleus, a prominent nucleus in the brain stem reticular formation at the level of the isthmus. This nucleus is composed entirely of norepinephrinergic neurons. Their fibers project to the spinal cord, brainstern, cerebellum, hypo­thalamus, thalamus, basal telencephalon, and the entire neocortex. The lateral tegmental system includes those norepinephrinergic neurons with cell bodies located in the dorsal motor nucleus of X, the nucleus of the solitary tract, and the adjacent and lateral tegmentum. The fibers of this system project to the spinal cord, brainstem, hypothalamus, thalamus, and basal telencephalon

Distribution of Dopaminergic Fibers

Dopaminergic systems in the CNS are more complex, numerous, and diversely distributed than norepinephrine systems. Seven _d_<?fla..!Jl:~I1.e~gj£ systems can be identified III the mammalian brain.

Nigrostriatal System The neurons in this system project from the pars compacta of the substantia nigra and the mediolateral tegmentum to terminate in the caudate nucleus, putamen, and globus pallidus. A marked reduction in dopamine content in the neostriatum (caudate and putamen) is characteristic in patients with Parkinson's disease. There is good evidence that the dopamin­ergic neurons of the substantia nigra inhibit their target cells in the caudate nucleus.

Mesocortical System This system is composed of fibers from the substan­tia nigra and medioventral tegmentum which do not project to the basal nuclei. The fibers terminate in both the neocortex and allocortex. Terminations in the former include the mesial frontal, anterior cingulate, entorhinal, and perirhinal regions. Terminations in the allocortex include the olfactory bulb, anterior ol­factory nucleus, olfactory tubercle, piriform cortex, septal area, and amygda­loid complex.

Tuberohypophyseal System These fibers originate in the arcuate and peri­ventricular hypothalamic nuclei, and project to the neurointermediate lobe of the pituitary gland as well as the median eminence. One function of this system appears to be the inhibition of pituitary prolactin secretion. The pathway to the intermediate lobe may serve to inhibit melanocyte-stimulating hormone (MSH) secretion.

Retinal System The dopaminergic neurons of this system are the in­terplexiform cells of the retina which terminate in both the inner and outer plex­iform layers of the retina.

Incertohypothalamic System These fibers project from the zona incerta and the posterior hypothalamus to the dorsal hypothalamic area and the sep­tum. They may playa role in neuroendocrine regulation.

Periventricular System The cell bodies of these fibers are located in the medulla in the area of the dorsal motor nucleus of X, the nucleus of the solitary tract, and the periaqueductal and periventricular gray matter. They terminate in the periaqueductal and periventricular gray, tegmentum, tectum, thalamus, and hypothalamus. Their function is unknown.

Olfactory Bulb System This system is composed of the periglomerular cells of the olfactory bulbs which terminate on the mitral cells of the glomeruli. Their function is unknown.

Serotonin and Melatonin

Serotonin and melatonin are neuroactive indolealkylamines. Serotonin functions as a CNS neurotransmitter while melatonin, formed by a two-step process from serotonin, may playa hormonal role in the pineal gland. The highest concentration of serotonin anywhere in the body is in the pineal gland. The next highest concentration is in the raphe nuclei of the lower brainstem. The French neurophysiologist Jouvet demonstrated the role of these serotonergic raphe neurons by performing experiments on cats. He selectively de­stroyed the raphe neurons, producing a significant reduction in brain serotonin levels, and found that the cats became totally insomniac. He followed this by administering p-chlorophenylalanine to another group of cats. This drug, which prevents the conversion of tryptophan to 5-hydroxytryptophan by interfering with the action of the enzyme tryptophan hydroxylase, decreases the raphe concentration of serotonin, because 5-hydroxytryptophan is a serotonin pre­cursor. This group of cats also became insomniac. Subsequent administration of 5-hydroxytryptophan reversed the insomnia, putting the cats to sleep.

Melatonin is formed from serotonin in the pineal gland by acetylization to n-acetyl serotonin by 5_hydroxytryptamin~-n-acetylase. The enzyme 5­hydroxyindole-o-methyl transferase then completes the conversion to mela­tonin. The synthesis of both serotonin and melatonin, as well as the degradation of serotonin, are illustrated in Fig. 17-7