Chapter 22: Cells of the Nervous System

Signaling at Synapses Is Terminated by Degradation or Reuptake of Neurotransmitters

Following their release from a presynaptic cell, neurotransmitters must be removed or destroyed to prevent continued stimulation of the postsynaptic cell. Signaling can be terminated by diffusion of a transmitter away from the synaptic cleft, but this is a slow process. Instead, one of two more rapid mechanisms terminates the action of neurotransmitters at most synapses.

Signaling by acetylcholine is terminated when it is hydrolyzed to acetate and choline by acetylcholinesterase, an enzyme localized to the synaptic cleft. Choline released in this reaction is transported back into the presynaptic axon terminus by a Na⁺/choline symporter and used in synthesis of more acetylcholine. The operation of this transporter is similar to that of the Na⁺-linked symporters used to transport glucose into cells against a concentration gradient (see Figure 11-26).

With the exception of acetylcholine, all the neurotransmitters shown in Figure 22-25 are removed from the synaptic cleft by transport back into the axon termini that released them. Thus these transmitters are recycled intact, as depicted in Figure 22-26 (step 5). Transporters for GABA, norepinephrine, dopamine, and serotonin were the first to be cloned and studied. These four transport proteins are all Na⁺-linked symporters. They are 60–70 percent identical in their amino acid sequences, and each is thought to contain 12 transmembrane α helices. As with other Na⁺ symporters, the movement of Na⁺ into the cell down its electrochemical gradient provides the energy for uptake of the neurotransmitter. To maintain electroneutrality, Cl⁻ often is transported via an ion channel along with the Na⁺ and neurotransmitter.

Neurotransmitter transporters are targets of a variety of drugs of abuse as well as many therapeutic drugs commonly used in psychiatry. Cocaine binds to and inhibits the transporters for norepinephrine, serotonin, and dopamine. In particular, binding of cocaine to the dopamine transporter inhibits reuptake of dopamine, causing a higher-than-normal concentration of dopamine to remain in the synaptic cleft and prolonging the stimulation of postsynaptic neurons. Long-lasting exposure to cocaine, as occurs with habitual use, leads to down-regulation of dopamine receptors and thus altered regulation of dopaminergic signaling. It is thought that decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize important brain reward circuits to the reinforcing effects of cocaine, leading to addiction. Similarly, therapeutic agents such as the antidepressant drugs fluoxetine (Prozac) and imipramine block serotonin reuptake, and the tricyclic antidepressant desipramine blocks norepinephrine reuptake. As a result, these drugs also cause a higher-than-normal concentration of neurotransmitter to remain in the synaptic cleft and prolong the stimulation of postsynaptic neurons. Fluoxetine and similarly acting drugs such as paroxetine (Paxil) and sertraline (Zoloft) are often referred to collectively as selective serotonin reuptake inhibitors (SSRIs).