Mental Health: A Report by the Surgeon General

Superimposed on this breathtaking structural complexity is the chemical complexity of the brain. As described above, electrical signals within neurons are converted at synapses into chemical signals which then elicit electrical signals on the other side of the synapse. These chemical signals are molecules called neurotransmitters. There are two major kinds of molecules that serve the function of neurotransmitters: small molecules, some quite well known, with names such as dopamine, serotonin, or norepinephrine, and larger molecules, which are essentially protein chains, called peptides. These include the endogenous opiates, Substance P, and corticotropin releasing factor (CRF), among others. All told, there appear to be more than 100 different neurotransmitters in the brain (Table 2-1 contains a selected list).

A neurotransmitter can elicit a biological effect in the postsynaptic neuron by binding to a protein called a neurotransmitter receptor. Its job is to pass the information contained in the neurotransmitter message from the synapse to the inside of the receiving cell. It appears that almost every known neurotransmitter has more than one different kind of receptor that can confer rather different signals on the receiving neuron. Dopamine has 5 known neurotransmitter receptors; serotonin has at least 14.

Table 2-1. Selected neurotransmitters important in psychopharmacology

Although there are many kinds of receptors with many different signaling functions, we can divide most neurotransmitter receptors into two general classes. One class of neurotransmitter receptor is called a ligand-gated channel, where “ligand” simply means a molecule (i.e., a neurotransmitter) that binds to a receptor. When neurotransmitters interact with this kind of receptor, a pore within the receptor molecule itself is opened and positive or negative charges enter the cell. The entry of positive charge may activate additional ion channels that allow more positive charge to enter. At a certain threshold, this causes a cell to fire an action potential—an electrical event that leads ultimately to the release of neurotransmitter. By definition, therefore, receptors that admit positive charge are excitatory neurotransmitter receptors. The classic excitatory neurotransmitter receptors in the brain utilize the excitatory amino acids glutamate and, to a lesser degree, aspartate as neurotransmitters. Conversely, inhibitory neurotransmitters act by permitting negative charges into the cell, taking the cell farther away from firing. The classic inhibitory neurotransmitters in the brain are the amino acids gamma amino butyric acid, or GABA, and, to a lesser degree, glycine.

Most of the other neurotransmitters in the brain, such as dopamine, serotonin, and norepinephrine, and all of the many neuropeptides constitute the second major class. These are neither precisely excitatory nor inhibitory but rather act to produce complex biochemical changes in the receiving cell. Their receptors do not contain intrinsic ion pores but rather interact with signaling proteins, called“G proteins” found inside the cell membrane. These receptors thus are called G protein-linked receptors. The details are less important than understanding the general scheme. Stimulation of G protein-linked receptors alters the way in which receiving neurons can process subsequent signals from glutamate or GABA. To use a metaphor of a musical instrument, if glutamate, the excitatory neurotransmitter, is puffing wind into a flute or clarinet, it is the modulatory neurotransmitters such as dopamine or serotonin that might be seen as playing the keys and, thus, altering the melody via G protein-linked receptors.

The architecture of these systems drives home this point. The precise brain circuits that carry specific information about the world and that are involved in precise point-to-point communication within the brain use excitatory or inhibitory neurotransmission. Examples of such circuits, which are massively parallel, can be found in the visual and auditory cortex. Overlying this pattern of precise, rapid (timing in the range of milliseconds) neurotransmission are the modulatory systems in the brain that use norepinephrine, serotonin, and dopamine. In each case, the neurotransmitter in question is made by a very small number of nerve cells clustered in a limited number of areas in the brain. Of the hundred billion neurons in the brain, only about 500,000, for example, make dopamine—that is, for every 200,000 cells in the brain, only one makes dopamine. Even fewer make norepinephrine. The cell bodies of the dopamine neurons are clustered in a few brain regions, most importantly, regions deep in the brain, in the midbrain, called the substantia nigra, and the ventral tegmental area. Norepinephrine neurons are made in the nucleus locus coeruleus even farther down in the brain stem in a structure called the pons. Serotonin is made by a somewhat larger number of nuclei but, still, not by many cells. Nuclei called the raphe nuclei spread along the brain stem. While each of these neurotransmitters is made by a small number of neurons with clustered cell bodies, each sends its axons branching throughout the brain, so that in each case a very small number of neurons, which largely appear to fire in unison when excited, influence almost the entire brain. This is not the picture of systems that are communicating precise bits of information about the world but rather are intrinsic modulatory systems that act via other G protein-linked receptors to alter the overall responsiveness of the brain. These neurotransmitters are responsible for brain states such as degree of arousal, ability to pay attention, and for putting emotional color or significance on top of cold cognitive information provided by precise glutaminergic circuits. It is no wonder that these modulatory neurotransmitters and their receptors are critical targets of medications used to treat mental disorders—for example, the antidepressant and antipsychotic drugs—and also are the targets of drugs of abuse.

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