Neurotransmitter Organization

There are three major chemical classes of neurotransmitters.

1. Amino acid transmitters: glutamate (GLU) and aspartate are recognized as the major excitatory

Figure 1

Synapse. Nerve ending from one neuron forms a junction, the synapse, with another neuron (the postsynaptic neuron). The synaptic junction is actually a small space, sometimes called the synaptic cleft. Neurotransmitter molecules are synthesized by enzymes in the nerve terminal, stored in vesicles, and released into the synaptic cleft when an eletrical impulse invades the nerve terminal. The electrical impulse originates in the neuronal cell body and travels down the axon. The released neurotransmitter combines with receptors on postsynaptic neurons, which are then activated. To terminate neurotransmission, transporters remove the neurotransmitter back into the nerve terminal that released it.

Figure 1

Synapse. Nerve ending from one neuron forms a junction, the synapse, with another neuron (the postsynaptic neuron). The synaptic junction is actually a small space, sometimes called the synaptic cleft. Neurotransmitter molecules are synthesized by enzymes in the nerve terminal, stored in vesicles, and released into the synaptic cleft when an eletrical impulse invades the nerve terminal. The electrical impulse originates in the neuronal cell body and travels down the axon. The released neurotransmitter combines with receptors on postsynaptic neurons, which are then activated. To terminate neurotransmission, transporters remove the neurotransmitter back into the nerve terminal that released it.

transmitting signals; GAMMA AmINOBUTYRATE (GABA) and glycine are the major inhibitory transmitters. These transmitter substances occur in concentrations of one millionth part per milligram (juJM/mg) protein. Since they are considered the most frequently employed transmitter substances, they have been linked to many aspects of the actions of addictive drugs.

2. Aminergic transmitters: ACETYLCHOLINE, epinephrine (also called adrenaline), NOREPINEPHRINE (also called noradrenaline), DOPAMINE, SEROTONIN, and histamine. The aminergic neurons constitute a minor population of neuronal transmission sites, as reflected in the fact that their concentrations in the brain are roughly 1/1000th that of the amino acid transmitters or one billionth part per milligram (nM/mg protein). Because of their divergent anatomy (a few clusters of aminergic neurons may project onto literally millions of target neurons in many locations of the brain) and the ability of their synaptic signals to produce long-lasting effects, the aminergic neurons represent a very powerful subset of transmission conditions that is important to the effects of addictive drugs. Of particular relevance are the dopaminergic neurons— for their pertinence to the sites of reward for stimulants, opiates, and certain aspects of etha-

nol (alcohol) action—and the noradrenergic and serotonergic neurons—for their association with the phenomena of drug adaptation and tolerance.

3. Neuropeptides: of which there are dozens. Peptides are molecules containing a specific series of 2-50 amino acids, chemically arranged in a specialized "head-to-toe" chemical linkage known as a peptide bond. The order and number of the linked amino acids determine the linear structure of the peptide. In the nervous system, peptides, in general, occur in still lower concentrations than do the two prior classes of transmitter, namely at 10-100 trillionth part per milligram (pM/mg) protein. A revolutionary finding has emerged here in concepts of brain system interactions: It would now seem that neuropeptides are almost certainly never the sole signal to be secreted by a central neuron that contains such a signaling molecule, but rather accompany either an amino acid or an amine transmitter (at intrasynaptic terminal concentrations a thousand to a millionfold higher), such sites may even contain a second or third peptide as well.

Neuropeptides are of interest to the molecular and cellular mechanisms of addictive drug and alcohol action, because they may provide the post-synaptic receptors through which the drugs act (as in the case of the opiates and possibly the case for the natural BENZODIAZEPINES) or modify the effects of the presynaptic transmitters (as in the case of the peptide cholecystokinin that accompanies some forms of dopaminergic transmission, through which stimulants act and may modify responses to that amine if cosecreted).

Because of the ability to read the linear sequences of the amino acids, it has become clear that many of the neuropeptides share select small sequences and thus conceptually constitute "families" of peptides. For example, the opioid peptides all share one or more repeats of the amino-acid sequence tyrosine -glycine-glycine-phenylalanine; thus, each of the opioid-peptide genes leads to the expression of a different pre-prohormone by different sets of neurons of the central and peripheral nervous system. The existence of the shared amino-acid sequences implies that at some point in evolution, there may have been only one opioid-peptide signal, which was then duplicated and modified for use by the increasing number of neurons that came with the evolution of the mammalian brain. Such family relationships also exist for other peptide families (oxytocin/vasopressin; the tachykinin peptides; the secretin/glucagon-related peptides; the pancreatic polypeptide-related pep-tides), whose amino-acid sequences have shown great conservation over large domains of the evolutionary tree, attesting to the high signal quality of these molecules and the transductive mechanisms of their receptors. Other peptides, such as somatostatin and gonadotropin-releasing hormone, have no known family relationships as yet—but the discovery process here is probably not complete.

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