Home > Encyclopedia of Drugs, Alcohol, and Addictive Behavior > Neurotransmission

NEUROTRANSMITTER ORGANIZATION

There are three major chemical classes of neurotransmitters.

1. Amino acid transmitters: glutamate (GLU) and aspartate are recognized as the major excitatory transmitting signals; GAMMA A MINOBUTYRATE (GABA) and glycine are the major inhibitory transmitters. These transmitter substances occur in concentrations of one millionth part per milligram (μM/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 ethanol (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 peptides), 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.

OTHER TRANSMITTER CANDIDATES

Other kinds of molecules may also be made within neurons to play auxiliary roles in intercellular transmission in the nervous system—from purines like Adenosine Triphosphate, lipids like arachidonic acid and prostaglandins, and steroids similar to those made and released by the adrenal cortex and the gonads. These substances may, in some cases, act as intracellular second messengers to underlie the effects of the aminergic and peptidergic transmitters (see below); they therefore have implicit relevance to the effects of the addictive drugs whether or not they may also serve as primary transmission signals.

Investigators have revealed that under some conditions active neurons may synthesize gaseous signals, such as nitric oxide and carbon monoxide, which can carry rapidly evanescent signals over short distances. The effects of these transmission-related substances will undoubtedly become of increasing importance to the explanations of the mechanisms of action or adaptation to the addictive drugs.

SIGNAL TRANSDUCTION ORGANIZATION

Aside from the chemistry of the neurotransmitter substances, further insight into their role in the actions of addictive drugs arises from the viewpoint of their synaptic physiology and their underlying mechanisms of signal transduction. When neurons respond to neurotransmitters, the ultimate changes in the excitability and metabolic activity of the responding neuron generally require changes into or out of the cell in the flow of ions (natural chemical elements of the extracellular fluid)—some with positive charge (sodium, potassium, and calcium) and others with negative charge (chloride).

As a general rule, it would appear that every neurotransmitter has more than one form of post-synaptic receptor through which its effects are mediated. Before the ability to characterize these receptors through molecular genetics, such receptor subtypes were identified on the basis of the comparative pharmacological potency of synthetic AGONISTS or ANTAGONISTS of the natural transmitter. With the advent of molecular cloning, however, an even finer subtyping would appear to be required, since many of the conclusions on receptor pharmacological patterns were based on analyses of tissue fractions that undoubtedly contained many molecular forms. A major effort in the future will be to link more explicitly the molecular and pharmacological characterization of neurotransmitter receptor subtypes and to determine which of them are most critical to the effects of, and adaptations to, addictive drugs.

Three major formats have been revealed for the transductive process.

1. Directly regulated ion channels. Here the ion channel to be opened is formed by the units of the receptor molecule itself, as recently established by direct cloning of several such receptor-ionophores. Such receptors are now known to be the motif of the nicotinic-cholinergic receptors of the neuromuscular junction and the central nervous system, as well as for the three types of glutamate receptor, the several isoforms of the GABA_A receptor, the glycine receptor, and at least one form of a serotonin receptor.

Common features of these receptors are (a) they are composed of several (3-5) subunits, called monomers, that apparently may be combined in differing ratios (so-called multimeric recombinations) by various neurons to constitute the "holoreceptor"; (b) each monomer consists of four presumed transmembrane domains; and (c) discrete sections of the receptor monomer, either within the membrane or the cytoplasm, account for their voltage and chemical sensitivity, and for the ease and duration of openings in the ion channel.

2. Indirectly regulated ion channel-receptors. This form is based on the similarities between the visual pigment rhodopsin—the molecule used by photoreceptor neurons (rods, cones) to transduce light into signals to other neurons of the retina—and the beta-adrenergic receptor—one of the types of receptors regulated by the amine norepinephrine. This general form of transducing molecule was later found to be the form also used by the cholinergic muscarinic receptor, as well as by most serotonin and all known dopamine receptors, plus all the known peptide receptors.

The common features of this class are (a) the receptor is a single molecule, with seven trans-membrane domains; (b) activation of these receptors by their signaling molecules leads to further interactions of the receptor with other large proteins, some of them enzymes, within or near the plane of the membrane; and (c) the eventual indirect regulation of the ion channel, either the opening or closing of the channel, is then mediated through small molecular intracellular second messengers, such as the calcium ion (Ca²⁺) or the products of the associated enzymes, yielding intracellular second-messenger molecules, such as cyclic adenosine monophosphate (cAMP), or a lipid such as an inositol phosphate, diacyl-glycerol, or an arachadonic acid catabolite. The essential common second step of such transduction cascades is that the activated receptor interacts with a guanosine triphosphate (GTP)-binding protein (termed a G-protein) composed of three monomer subunits. The G-protein complex dissociates to activate the enzyme making the second messenger and, at the same time, hydrolyses the GTP and re-associates to end the cycle of signal generation. The second messenger consequences of this form of transduction, however, may be more enduring—activating one or more enzymes (protein kinases or phosphatases) that can add or remove phosphate groups on structural proteins or other enzymes, to activate or inactivate them. Such events can significantly shift the metabolic state of the responding cell and eventually regulate the expression of its specific genes. One such gene target is the immediate early genes of the nervous system, the protooncogenes, discovered some years ago because of the mutated forms used by oncogenic viruses, which induce cancer in non-neuronal cells.

3. The receptor-enzyme. This third major molecular motif of signal transduction has been elucidated recently; although it is already clear that this form does exist in the mammalian brain, it has been studied more in non-neuronal systems. This motif's characteristics are that the receptor for some peptides is itself the enzyme guanylate cyclase, which is directly activated by receptor-ligand binding, leads to an intracellular generation of cyclic guanosine monophosphate, and then to a cascade of events similar to that described for AMP.

SYNAPTIC INTERACTIONS

Most neurons receive synaptic input simultaneously from hundreds of other neurons, each of which employs its own mix of transmitters. The transductive processes underlying these individual events can influence the intensity and duration of the subsequent responses, thereby integrating incoming signals and providing the basis by which activity in assemblies of interconnected neurons results in behavioral output by the brain.

To gain insight into the basis by which the events of neurotransmission can lead to multineuronal programs of interaction, such as those required to initiate responding for an addictive drug, requires knowledge both of the anatomical substrate over which such programs of neuronal activity take place and of the effects of the neurotransmitters at each of the cellular elements of such an interactive ensemble of neurons.

(SEE ALSO: Addiction: Concepts and Definitions; Brain Structures and Drugs; Limbic System; Tolerance and Physical Dependence)

FLOYD BLOOM