Neurotransmitters

Neurotransmitters are chemicals made by neurons and used by them to transmit signals to the other neurons or non-neuronal cells (e.g., skeletal muscle; myocardium, pineal glandular cells) that they innervate. The neurotransmitters produce their effects by being released into synapses when their neuron of origin fires (i.e., becomes depolarized) and then attaching to receptors in the membrane of the post-synaptic cells. This causes changes in the fluxes of particular ions across that membrane, making cells more likely to become depolarized, if the neurotransmitter happens to be excitatory, or less likely if it is inhibitory.

Neurotransmitters can also produce their effects by modulating the production of other signal-transducing molecules (“second messengers”messengers”) in the post-synaptic cells (Cooper, Bloom and Roth 1996). Nine compounds — belonging to three chemical families — are generally believed to function as neurotransmitters somewhere in the central nervous system (CNS) or periphery. In addition, certain other body chemicals, for example, adenosine, histamine, enkephalins, endorphins, and epinephrine, have neurotransmitter-like properties, and many additional true neurotransmitters may await discovery.

The first of these families, and the group about which most is known, is the amine neurotransmitters, a group of compounds containing a nitrogen molecule which is not part of a ring structure. Among the amine neurotransmitters are acetylcholine, norepinephrine, dopamine, and serotonin.

Acetylcholine is possibly the most widely used neurotransmitter in the body, and all axons that leave the central nervous system (for example, those running to skeletal muscle, or to sympathetic or parasympathetic ganglia) use acetylcholine as their neurotransmitter. Within the brain acetylcholine is the transmitter of, among other neurons, those generating the tracts that run from the septum to the HIPPOCAMPUS, and from the nucleus basalis to the CEREBRAL CORTEX — both of what basal is to the CEREBRAL CORTEX — both of which seem to be needed to sustain memory and learning. It is also the neurotransmitter released by short-axon interneurons of the BASAL GANGLIA.

Norepinephrine is the neurotransmitter released by sympathetic nerves (e.g., those innervating the heart and blood vessels) and, within the brain, those of the locus coeruleus, a nucleus activated in the process of focussing attention.

Dopamine and Serotonin apparently are neurotransmitters only within the CNS. Some dopaminergic (i.e., dopamine-releasing) neurons run from the substantia nigra to the corpus striatum; their loss gives rise to the clinical manifestations of Parkinson’s Disease (Korczyn 1994); others, involved in the rewarding effects of drugs and natural stimuli, run from the mesencephalon to the nucleunucleus accumbens.

Dopamine

Dopaminergic neurons involved in the actions of most antipsychotic drugs (which antagonize the effects of dopamine on its receptors) run from the brain stem to limbic cortical structures in the frontal region, while the dopamine released from hypothalamic cells travels via a private blood supply, the pituitary portal vascular system, to the anterior pituitary gland, where it tonically suppresses release of the hormone prolactin. (Drugs that interfere with the release or actions of this dopamine can cause lactation as a side-effect, even in men.)

Serotonin

Studies have linked low levels of serotonin in the brain to abnormal behaviors, such as: depression, suicide, impulsive aggression, alcoholism, sexual deviance, and explosive rage. High levels of serotonin have been associated with masked aggression, obsessive compulsion, fearfulness, lack of self-confidence, and shyness.

The cell bodies, or perikarya, of serotoninergic (serotonin-releasing) neurons reside in the brain stem; their axons can descend in the spinal cord (where they “gate” incoming sensory inputs and also decrease sympathetic nervous outflow, thus lowering blood pressure) or ascend to other parts of the brain. Within the brain such serotoninergic nerve terminals are found in virtually all regions, enabling this transmitter to modulate a wide variety of behavioral and non-behavioral functions including, among others, the mood; sleep; total food intake and macronutrient (carbohydrate vs. protein) selection (Wurtman and Wurtman 1989); aggressive behaviors; and PAIN sensitivity (Frazer, Molinoff, and Winokur 1994).

Brains of women produce only about two-thirds as much serotonin as those of men (Nishizawa et al. 1997); this may explain their greater vulnerability to serotonin-related diseases like depression and obesity. Within the pineal gland serotonin is also the precursor for the sleep-inducing hormone melatonin (Dollins et al. 1994).

The second neurotransmitter family includes amino acids, compounds that contain both an amino group (NH2) and a carboxylic acid group (COOH) and which are also the building blocks of peptides and proteins. The amino acids known to serve as neurotransmitters are glycine, glutamic and aspartic acids, all present in all proteins, and gamma-amino butyric acid (GABA), produced only in brain neurons. Glutamic acid and GABA are the most abundant neurotransmitters within the central nervous system, particularly in the cerebral cortex; glutamic acid tends to be excitatory and GABA inhibitory. Aspartic acid and glycine subserve these functions in the spinal cord (Cooper, Bloom, and Roth 1996).

The third neurotransmitter family is composed of peptides, compounds that contain at least two and sometimes as many as 100 amino acids. Peptide neurotransmitters are poorly understood: Evidence that they are, in fact, transmitters tends to be incomplete, and restricted to their location within nerve terminals, and the physiologic effects produced when they are applied to neurons. Probably the best-understood peptide neurotransmitter is substance P, a compound that transmits signals generated by pain.

In general, each neuron uses only a single compound as its neurotransmitter. However, some neurons contain both an amine and a peptide, and may release both into synapses. Moreover, many neurons release adenosine, an inhibitory compound, along with their “true” transmitter, for instance, norepinephrine or acetylcholine. The stimulant effect of caffeine results from its ability to block receptors for this adenosine.

Neurotransmitters are manufactured from circulating precursor compounds like amino acids, glucose, and the dietary amine choline. Neurons modify the structure of these precursor compounds through a series of enzymatic reactions that often are limited not by the amount of enzyme present but by the concentration of the precursor — which can change, for example, as a consequence of eating (Wurtman 1988). Neurotransmitters that come from amino acids include serotonin, which is derived from tryptophan; dopamine and norepinephrine, which are derived from tyrosine; and glycine, which is derived from threonine. Among the neurotransmitters made from glucose are glutamate, aspartate, and GABA. Choline serves as a precursor for acetylcholine.

Once released into the synapse, each neurotransmitter combines chemically with one or more highly specific receptors; these are protein molecules which are embedded in the post-synaptic membrane. As noted above, this interaction can affect the electrical properties of the post-synaptic cell, its chemical properties, or both. When a NEURON is in its resting state, it sustains a voltage of about -70 millivolts as the consequence of differences between the concentrations of certain ions at the internal and external sides of its bounding membrane. Excitatory neurotransmitters either open protein-lined channels in this membrane, allowing extracellular ions, like sodium, to move into the cell or close channels for potassium. This raises the neuron’s voltage toward potassium. This raises the neuron’s voltage towards zero, and makes it more likely that — if enough such receptors are occupied — the cell will become depolarized. If the postsynaptic cell happens also to be a neuron (i.e., as opposed to a muscle cell), this depolarization will cause it to release its own neurotransmitter from its terminals. Inhibitory neurotransmitters like GABA activate receptors that cause other ions — usually chloride — to pass through the membrane; this usually hyperpolarizes the postsynaptic cell and decreases the likelihood that it will become depolarized. (The neurotransmitter glutamic acid, acting via its NMDA receptor, can also open channels for calcium ions. Some investigators believe that excessive activation of these receptors in neurological diseases can cause toxic quantities of calcium to enter the cells, and kill them.)

If the postsynaptic cell is a muscle cell rather than a neuron, an excitatory neurotransmitter will cause the muscle to contract. If the postsynaptic cell is a glandular cell, an excitatory neurotransmitter will cause the cell to secrete its contents.

While most neurotransmitters interact with their receptors to change the voltage of post-synaptic cells, some neurotransmitter interactions, involving a different type of receptor, modify the chemical composition of the postsynaptic cell by either causing or blocking the formation of ‘second messenger’ molecules.

These second messengers regulate many of the postsynaptic cell’s biochemical processes, including gene expression; they generally produce their effects by activating enzymes that add high-energy phosphate groups to specific cellular proteins.

Examples of second messengers formed within the postsynaptic cell include cyclic adenosine monophosphate, diacylglycerol, and inositol phosphates. Once neurotransmitters have been secreted into synapses and have been secreted into synapses and have acted on their receptors, they are cleared from the synapse either by enzymatic breakdown — for example acetylcholine, which is converted by the enzyme acetylcholinesterase to choline and acetate, neither of which has neurotransmitter activity — or, for neurotransmitters like dopamine, serotonin and GABA, a physical process called reuptake. In reuptake, a protein in the presynaptic membrane acts as a sort of sponge, causing the neurotransmitter molecules to reenter their neuron of origin, where they can be broken down by other enzymes (for example monoamine oxidase, in dopaminergic, serotoninergic, or noradrenergic neurons) or repackaged for reuse.

As indicated above, particular neurotransmitters are now known to be involved in many neurological and behavioral disorders. For example, in Alzheimer’s disease, whose victims exhibit loss of intellectual capacity (particularly short-term memory), disintegration of personality, mental confusion, hallucinations, and aggressive — even violent — behaviors, many families of neurons, utilizing many neurotransmitters, die (Wurtman et al. 1996). However, the most heavily damaged family seems to be the long-axon acetylcholine-releasing neurons, originating in the septum and the nucleus basalis, which innervate the hippocampal and cerebral cortices. Acetylcholinesterase inhibitors which increase brain levels of acetylcholine can improve short-term memory, albeit it can improve short-term memory, albeit transiently, in some Alzheimer’s disease patients.

Most drugs — therapeutic or recreational — that affect brain and behavior do so by acting at synapses to affect the production, release, effects on receptors, or inactivation of neurotransmitter molecules (Bernstein 1988). Such drugs can also constitute important and specific probes for understanding cognition and other brain functions.

5HT

5-HT is broken down by MAO-A, but the MAO-A is located in vesicles in the axon terminus, so requires reuptake of the 5-HT from the synapse prior to degradation. Acetylcholinesterase, on the other hand, operates in the synapsther hand, operates in the synapse itself.