The Addicted Brain (7 page)

Neurotransmitter Synthesis and Storage

The way that neurotransmitters are synthesized depends on which neurotransmitter you are considering. Small molecule neurotransmitters such as dopamine, which is critical for the addiction process (discussed later), are made from amino acid precursors through the actions of enzymes. An enzyme is nothing more than a protein that makes new molecules by facilitating molecular changes. The changes that are made can result in building structures by adding atoms or joining smaller molecules together. Conversely the changes can be a
breakdown
of
molecules by removing atoms or by splitting off parts of molecules. Several enzymes often act in a sequence to produce neurotransmitter molecules, which are unique structures. The substances produced and altered along the way are referred to as intermediates. For example, dopamine is made from a widely occurring amino acid, tyrosine. An OH (hydroxyl, oxygen, and hydrogen bound together) group is added to the tyrosine by the enzyme tyrosine hydroxylase to produce the intermediate dihydroxyphenylalanine (DOPA). Then that intermediate is acted upon by the enzyme DOPA decarboxylase to produce dopamine. Because each neurotransmitter has a unique structure, it is synthesized by its own unique set of enzymes and processes. The enzymes and processes needed for the production of neurotransmitters usually are found in the cell body of the neuron, which is where neurotransmitters are produced.

Neurotransmitters are powerful and even dangerous in that they can profoundly alter neuronal function through their signaling properties, especially if they interact with receptors in the wrong place and at the wrong time. Since such stray neurotransmitters could create signaling confusion, the neurons use storage vesicles which are small, membrane-bound containers capable of sequestering large amounts of neurotransmitters. Neurotransmitters are synthesized usually in the cell body and shipped in storage vesicles to the nerve terminals for action-potential-regulated release of neurotransmitters into the synapse.

Many Different Neurotransmitters

There is a surprising variety of neurotransmitters. They can be small molecules such as dopamine, or, they can be mega-molecules such as endorphin, which are equivalent to multiples of molecules the size of dopamine. They can even be gases such as nitric oxide (NO). Some neurotransmitters are excitatory (they excite the next neuron in the circuit) such as glutamate, and others are inhibitory such as gamma-aminobutyric acid (GABA). Having both excitatory and inhibitory signals enables greater control over neuronal activity.

Although it is not surprising that there is more than one neurotransmitter, it appears that there are dozens of neurotransmitters, which is somewhat of a surprise. Scientists speculate that neurotransmitters, in general, are so important for brain function that evolution has provided us with many. They might provide a
margin of safety
so that if a genetic mutation deletes one neurotransmitter, we are not totally impaired.

If our goal is to understand how different drugs of abuse work in the brain, we need to know about neurotransmitters because each drug of abuse can be linked to altering the actions of specific neurotransmitters (see
Table 4-1
).

Table 4-1. Drugs of Abuse and Related Neurotransmitters

Drugs that are abused and cause addiction interfere with the action of some neurotransmitter. Each drug in a particular class affects the same neurotransmitter. Occasionally, a single drug can affect more than one neurotransmitter.

Receptors—How Neurotransmitters Work

The gold at the end of the neurotransmission rainbow is the receptor, which is a protein that is selective for a given neurotransmitter just as a given key is selective for a certain lock. A
receptor for dopamine will not bind to the neurotransmitter glutamate or any other neurotransmitter for that matter. When a neurotransmitter is released, it diffuses across the synaptic cleft (see
Figure 4-1
, right) and binds to its receptor. When the neurotransmitter binds, and this is the important part, it changes the shape of the receptor so that the receptor produces some change in the neuron. So the receptor (along with the neurotransmitter, of course) is the element that induces and mediates the change in the next neuron in the circuit. It is also important to know that the neurotransmitters bind to the receptors
reversibly
so that after they act at the receptor and induce a postsynaptic change, they then move away from the receptor. The significance of this is discussed later in this chapter.

There are several different kinds of receptors categorized by the way they work or their structure. Two major kinds are the ion channel receptors and the G-protein coupled receptors. Ion channel receptors were named because when the neurotransmitter binds, it opens an ion channel, which is part of the receptor, and ions flow through it and thereby change the electrical charge in the neuron (see
Figure 4-2
). Ion channel receptors work quickly (in milliseconds) and are responsible, for example, for the contraction of muscles and movements.

Figure 4-2. Neurotransmitter receptors mediate signaling from one neuron to the next.
This figure shows one of the major kinds of receptors in the brain, the ligand-gated ion channel receptor, which does exactly as its name implies. When the neurotransmitter that is released from the previous neuron binds to the receptor, a gate opens and the channel in the receptor allows the passage of ions that change the electrical charge and voltage across the membrane. This in turn can cause an action potential (electrical impulse) in the postsynaptic cell. This is one example of how a neurotransmitter released from one neuron can change the properties of the next neuron through a receptor. (Adapted from
http://en.wikipedia.org/wiki/File:Three_conformation_states_of_acetylcholine_receptor.jpg
.)

The other major class of receptors is the G-protein coupled receptors (GPCRs). They are so named because they involve G-proteins in their signaling. The overall process is somewhat slow, occurring over seconds sometimes. When the neurotransmitter binds, the subsequent shape change in the receptor allows the G-protein—which is inside the cell and reversibly attached to the receptor—to become activated; then the activated G-protein diffuses in the nerve cell body and induces many different functions. Just as there are many different neurotransmitters, there are also many different G-proteins. This provides neurons with a marvelous variety of ways to produce needed changes. This variety is even greater because an individual neurotransmitter such as dopamine can have many subtypes of receptors that use different kinds of intracellular signaling!

In any case, the important thing for those of us focusing on drug abuse is that there are many kinds of signaling and receptors in the brain. They are complex and varied, and, you can say, offer many opportunities for abused drugs to influence the brain. Knowing all of the different kinds of receptors is not critical for knowing how drugs act, but knowing about receptors in general is important.

Removing Neurotransmitters—Making the Message Discreet

Neurotransmitters bind to their receptors in a reversible fashion—they go on and come off. Because the concentration of neurotransmitters is so high in the synaptic space immediately after release, the receptors get stimulated even though the neurotransmitters don’t stay on the receptors forever. After the neurotransmitters are bound to the receptors, signals occur, but—and this is significant—the signals
must be terminated
by removal of the neurotransmitters from the receptors and the synapse. If neurotransmission is not terminated, its action is not discrete, and might simply appear to be noise. The ways that the neurotransmitters can be removed from the receptor include the breakdown of the neurotransmitter into inactive products, removal from the synapse by reuptake for recycling, or by diffusion away from the receptors out of the synaptic space. Neurotransmitter breakdown requires enzymes, and reuptake requires a transporter, which is a protein in the nerve terminal membrane that transports the neurotransmitter back into the nerve terminal where it is again stored in vesicles. It is released again by the next action potential.

When we think of a neurotransmitter that is inactivated by being broken down, we often think of acetylcholine, historically the first substance believed to be a neurotransmitter. Like other neurotransmitters, it has several subtypes of receptors in different parts of the body, but its mechanism of termination is always the same. Acetylcholine is broken down by the enzyme acetylcholinesterase (see
Figure 4-3
) into inactive pieces.

Figure 4-3. Enzymatic breakdown of acetylcholine.
The molecular structure of the neurotransmitter acetylcholine is shown. A globular model of the enzyme, acetylcholinesterase (AChE) is shown breaking down acetylcholine into two smaller molecules, acetate and choline. Neither acetate nor choline are active at receptors so neurotransmission is effectively terminated by AChE, which is present in the synaptic cleft. (Image adapted from
www.proteopedia.org/.../Acetylcholinesterase
, accessed March 14, 2009.)

Another kind of neurotransmitter is called a peptide, which is often very large. Peptides are broken down by a specific set of enzymes called peptidases. They basically chop up the peptide neurotransmitters into smaller pieces so that they aren’t functional any more.

Reuptake is a process of termination that has been linked to many neurotransmitters. For example, dopamine, a neurotransmitter connected to drug abuse and addiction, is removed from the synapse by reuptake via a transporter appropriately called the dopamine transporter (DAT) (see
Figure 4-1
, right). The transporter is like a pump that moves the neurotransmitter from outside the nerve terminal back inside. This removes the neurotransmitter from the receptors and effectively stops its action. Psychostimulant drugs, such as cocaine, amphetamine, and methamphetamine, are well known to block this transporter, resulting in an excess of dopamine in the synapse.