Following electrical stimulation, all neurotransmitters are released into a gap between nerve cells known as the synaptic cleft. Once the neurotransmitter diffuses across the cleft, biological action is produced by interaction of the neurotransmitter with a signaling molecule known as a receptor. After the receptor has been activated, the neurotransmitter must be eliminated so that the cleft is clear, and the process can be repeated if necessary.

There are two prominent processes for removing neurotransmitters, and both are thought to play a role in the cases of serotonin and norepinephrine. The first of the processes is pretty much a recycling event, and is frequently called re-uptake or transport. The second process is metabolism, and in the cases of serotonin and norepinephrine, the enzyme monoamine oxidase (MAO) is important in metabolizing (or breaking down) the neurotransmitters. There are two (or more) isoforms of the enzyme, MAOA and MAOB. These two forms of MAO have distinct preferences for substrates and are inhibited differently by some inhibitors. MAOA is more effective in metabolizing serotonin; therefore, inhibition of this type of MAO has particular relevance for treating depression.

Strategies For Treating Depression

Synthetic Drugs:
The well-known drug category of the tricyclic anti-depressants represents a prime example of pharmacological blockage of the re-uptake processes. Tricyclics such as imipramine (Tofranil) and amitryptaline (Elavil) block transport of both serotonin and norepinephrine, thereby effectively increasing the levels of these neurotransmitters in the synaptic cleft. Newer anti-depressant drugs like fluoxetine (Prozac), sertraline (Zoloft), or paroxetine (Paxil) are much more specific for the serotonin re-uptake process. By blocking this transporter, they raise serotonin levels without having much effect on norepinephrine or other neurotransmitters. Consequently, the newer drugs are often called SSRI’s for selective serotonin re-uptake inhibitors.

An example of a drug which inhibits the metabolic enzyme MAO is tranylcypromine (Parnate). By blocking MAO, this drug slows metabolism of serotonin and norepinephrine, again elevating the levels of these neurotransmitters in the cleft. It should be pointed out, though, that other neurotransmitters like dopamine are also metabolized by MAO, so MAO inhibitors are fairly non-specific in their actions.

Mechanistic explanations of anti-depressant drug action may not be completely explained by reference to transport and MAO effects, however. Most anti-depressant drugs take weeks for full clinical effectiveness, while drug actions at the transport and MAO levels can occur in a few minutes to a few hours. Neurotransmitter physiology is subject to complex feedback and fine tuning processes, all of which have yet to be accounted for by research. So, we need to be cautious about assuming that anti-depressant drugs completely yield their effects, as conventional wisdom would suggest, by blocking transport and/or inhibiting MAO.

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