CONNECTIONS BETWEEN NERVE CELLS

CONNECTIONS BETWEEN NERVE CELLS

The dendritic, or receiving, area of neurons is where axons (transmitting fibers) from other nerve cells make contact. These points of contact are called synapses. A single synapse is, in itself, a complex structure, consist­ing of the presynaptic and the postsynaptic regions. The presynaptic region is the termination point of the axon of the transmitting cell, and at that point the axon balloons from a very small fiber to a group of bulblike endings called the presynaptic terminals. These terminals contain chemi­cals^—neurotransmitters—that are released into the space between the presynaptic terminal and the dendrite of the postsynaptic (receiving) cell. The neurotransmitter molecules react with special receptors that are sen­sitive only to that neurotransmitter on the postsynaptic cell, and, in just

thousandths of a second, these receptors cause electrical and/or biochem­ical signals within the receiving cell.

A single neuron can have a large number of synapses on its dendrites, and it is the job of the neuron cell body to take in signals from all of those synapses and make a decision. That decision is whether to fire electrical signals itself down its transmitting fiber—its axon. The signals that are transmitted down the axon are called action potentials because they can cause action somewhere else. If they come from a nerve cell synapsing onto a muscle cell, they can cause the muscle cell to contract. If they come from a nerve cell connecting to another nerve cell, they can cause that follower

nerve cell to either fire or stop firing, depending on what kind of signal it gets from the neurotransmitter molecules.

Thus, the input to a neuron is from synaptic connections from other neurons, while the output is a series of action potentials firing down its axon. The action potentials are all the same, just quick (about one-thou­sandth of a second) discharges of electrical activity'. The information is carried at the rate by which these discharges occur. So, if a neuron fires lots of action potentials in a brief period (up to four hundred in one sec‑

ond), it can have a large influence on its follower cells, while slow firing would have less influence.  Some drugs may affect the generation and spread of action potentials down the axon, but that is not a common site of drug action. These drugs usually produce drastic and often toxic changes because they can com­pletely stop a neuron from firing. One interesting toxin that does this is the chemical present in the ovaries of puffer fish, which are delicacies in Japan. This chemical, called tetrodotoxin, is so toxic that eating just part of a fish can paralyze the muscles responsible for breathing and lead to death. Japanese restaurants have chefs who are specially trained and licensed to remove the ovaries before the fish is served. This same class of toxin is also thought to be used in Haitian voodoo rituals to induce

zombie-like behavior.

Most drugs act either at the presynaptic terminal, where the neu­rotransmitter is released, or at the postsynaptic membrane on the neu­rotransmitter receptor. The synapse is the primary site of action of the majority of drugs that affect human brain functions. So to understand how drugs affect our CNS, we must understand the synapse.

The presynaptic terminal is the place where neurotransmitters are syn­thesized, packaged, and released. When action potentials travel from the cell body of the transmitting neuron down to the terminal area, the elec­trical signals cause changes in the shape of protein molecules that reside in the terminal area. These molecules sense the electrical signals and, within thousandths of a second, reconfigure themselves to form pores, or channels, in the terminal membrane. Calcium ions flow into the terminal through these pores, and the calcium initiates a chain of biochemical reactions. The result of this biochemical sequence is that packets of neu­rotransmitter molecules break through the terminal membrane and move toward the postsynaptic area of the receiving cell.

What happens to the neurotransmitter molecules after they are released? After all, if they stayed around forever, the postsynaptic neuron, or muscle fiber, would constantly be under their influence and further signaling would be impossible. Removal of neurotransmitters is accom­plished in three ways. First, the molecules just diffuse away into other areas where there are no receptors and are removed by the general circu­lation of fluids in the brain. Second, there can be specific chemicals that break the neurotransmitters into noneffective parts that are returned to the cells. Finally, there are specific sites on the presynaptic terminal that attach to the active neurotransmitter molecules and transport them back into the terminal for release again. These transport sites are often places where drugs act to prolong the presence of the transmitter in the postsyn‑  The electrical action at the synapse can thus control whether a cell starts to fire action potentials. For example, if a receptor opens a channel that lets in ions that make the cell less negative, then the electrical poten­tial of the cell moves in the direction of firing action potentials. If the receptor opens a channel that causes the cell to become more negative inside, then the cell becomes less able to fire. Clearly, then, with many synapses, the cell must add all of this electrical activity together, and the sum of it determines whether a cell fires. This addition of pro- and antifir­ing (excitatory and inhibitory) currents occurs in and around the cell body of the neuron, in a place where action potentials originate. Thus, all of the synaptic activity of the cell converges to the cell body, where the cell makes the decision to fire or not to fire, depending on the voltage across its cell membrane.

The two most common neurotransmitters in the CNS are the amino acids GABA (gamma-aminobutyric acid) and glutamate. These are referred to as inhibitory (GABA) and excitatory (glutamate) amino acid neurotransmitters. These neurotransmitters are responsible for much of the second-to-second processing in the CNS. If either of these is signifi­candy blocked, the proper functioning of the CNS is dramatically dis­rupted. There are many subtypes of these receptors, and each of these subtypes has different characteristics. Some of the most interesting drug effects come from activating just a particular subtype of a receptor rather than the whole class of receptors.

Receptors can initiate a cascade of biochemical events within neurons. Either by letting calcium ions into cells or by activating intracellular enzymes directly, activated receptors can profoundly change the biochem­ical environment of a cell. These biochemical signals can alter the num­bers of receptors for different transmitters, change the degree to which they recognize their transmitters, or even change the systems that regulate the genetics of the cell—literally, thousands of different processes. It is no

wonder that drugs that interact with receptors can be so specific and so powerful.

It is this diversity of receptors and biochemical signaling pathways that allows humans to devise drugs that have quite specific effects. Through­out this book there are references to actions of a drug at a specific recep­tor, receptor regulation site, or biochemical-signaling pathway. Although we know much about the way these chemicals operate, it is important to remember the mantra of every pharmacologist: "Every drug has two effects—the one I know about and the one I don't know about."