Let us now look at some examples of the actions of neurotransmitters. (You will also encounter other examples this quarter, when we talk about the skeletal muscles, opioid peptides in pain, neurotransmitters in sleep, and autonomic neurons.)
The neurotransmitter glutamate is the most common excitatory neurotransmitter in the brain and large amounts are released during a stroke. This is because neurons begin to run out of energy after a clot blocks the blood vessel serving the region. Lacking energy, the Na+/K+ active transporters can no longer maintain the normal ion concentrations, and the neurons become depolarized. Depolarization, of course, is the factor that triggers neurotransmitter release.
As glutamate is released and diffuses out from the region of stroke, the glutamate acts on neurons that were not directly damaged by the stroke. First, the glutamate depolarizes neurons by acting on ligand-gated ion channels that are responsible for fast postsynaptic potentials. As shown in the figure to the right, these are similar to the five subunit ion channels that respond to acetylcholine in skeletal muscle. Many neurotransmitter receptors are of this type.
A common postsynaptic receptor of this type is called the AMPA receptor. As a ligand-gated ion channel, it opens quickly when glutamate appears and allows Na+ to flow into the neurons. Due to the abundant glutamate present, there is a prolonged depolarization of the affected neurons.
Prolonged depolarization is exactly the factor that leads to the opening of NMDA receptors in neurons with this additional type of glutamate receptor. Recall that prolonged depolarization causes the Mg++ to move out of the channel, causing the channel to be open.
But the ion that flows through the NMDA channels is Ca++. In normal physiology, Ca++ is often an intracellular signalling molecule. But only brief puffs cause neurotransmitter release or muscle contraction. Steady levels of Ca++ are completely different. They activate a caspase, which leads to apotosis. Cells respond in this way because a steady level Ca++ inside the cell is an indication the plasma membrane is hopelessly damaged.
Thus, as a result of the glutamate release, the area of damaged neurons expands.
Epilepsy is defined as a chronic disorder characterized by spontaneous, recurrent discharges of large groups of cerebral neurons, and usually associated with some alteration of consciousness. Such neuronal discharges also are often called a seizure. Sometimes a specific cause can be identified, such as meningitis, a metabolic disorder, or a toxin. But more commonly there is no clear explanation.
Electrical recordings during seizures reveal that groups of neurons in the neocortex or hippocampus fire synchronously during a seizure. As a seizure begins, there is excessive stimulation of AMPA receptors, and then eventually NMDA receptors contribute as the seizure intensifies. Measurements of the interstitial fluid show a decrease in Ca++.
A number of neurochemical factors can induce seizures experimentally, and these provides a sense of the types of problems involved. The following, for example, can induce seizures:
As described above glutamate is the most abundant excitatory neurotransmitter in the brain and spinal cord. On the other hand, the most abundant inhibitory neurotransmitter is GABA.
QUESTION: During a seizure, why is the overactivity of NMDA receptors delayed relative to AMPA receptors?
QUESTION: Domoate is a toxin concentrated in mussels, and it tends to activate AMPA and NMDA receptors. Would you expect it to promote or suppress seizures?
QUESTION: In tissue surgically removed from an epileptic focus, would you expect to find upregulation or downregulation of AMPA and NMDA receptors?
QUESTION: From the above, you might expect a drug that increases the opening of GABA receptors to help in epilepsy. Can you name such a drug?
(Other drugs used in epilepsy tend to act on voltage-gated Na+ channels or voltage gated Ca++ channels.)
(From the above, you might wonder why glutamate antagonists can't be used as for epilepsy. Actually, blockers of both AMPA and NMDA receptors do suppress seizures in certain animal studies, but have not proven to be useful clinically.)
Phenothiazines, such as chlorpromazine, began to be used to treat psychotic disorders such as schizophrenia and bipolar disorders in the 1950s, and by the 1960s had greatly reduced the number of institutionalized patients. They have sedative effects as well. They act as dopamine receptor antagonists, although they do have other actions.
The dopamine receptors are all seven transmembrane domain proteins linked to trimeric G proteins. Thus they create slow EPSPs. This should not be surprising in neural circuits involved in emotions and motivations, where changes occur over seconds or longer.
Dopamine is structurally related to epinephrine and norepinephrine, which also act via seven transmembrane domain receptors coupled to trimeric G proteins.
There are a number of categories of antidepressant medications. We will briefly look at two.
The most important are selective serotonin reuptake inhibitors, such as fluoxetine (Prozac). These block the transporter that transfers the neurotransmitter serotonin from the synaptic cleft to the cytosol of the presynaptic terminal. Thus, they increase the action of serotonin in the synaptic cleft. Serotonin also acts on seven transmembrane domain receptors linked to a trimeric G proteins.
The tricyclic antidepressants began to be used for depression in the 1950s. They are now less likely to be used for depression than newer types of drugs. They are also used sometimes for neuropathic pain and other uses. The tricyclic antidepressants block reuptake transporters for serotonin and norepinephrine.