How Reuptake Inhibitors Decrease Neurotransmitter Levels
Monoamine Oxidase (MAO) and the Catecholamine O-Methyl Transferase
(COMT) enzymes metabolize (i.e., destroy and remove) serotonin, dopamine, norepinephrine, and epinephrine. These monoamine neurotransmitters are relatively stable and are not metabolize (destroyed) until they come in contact with the MAO and COMT enzymes. When neurotransmitters are in the vesicles of the pre-synaptic neuron, they are not exposed to metabolism by the MAO and COMT enzymes; they are safe and stable.
However, when neurotransmitters are in the synapse between the pre-synaptic and post-synaptic neuron, they are exposed to enzymatic metabolism, which leads to the depletion of neurotransmitters if proper levels of amino acid precursors are not administered to compensate for this process.24
In depressed patients (as well as people suffering from all disorders relating to neurotransmitter imbalance, including trichotillomania), synaptic neurotransmitter levels are not high enough to prevent disease symptoms, as illustrated in figure 2. Treatment with reuptake inhibitors leads to a decrease in presynaptic neurotransmitter levels (where they are safe from enzymatic metabolism) and an increase in the number of neurotransmitters in the synapse, as illustrated in figure 2. The blocking of neurotransmitter reuptake increases synaptic levels and the probability that neurotransmitters will experience enzymatic metabolism (i.e., be destroyed).
Figure 2: The effects of reuptake inhibitors on neurotransmitter levels, reuptake inhibition may deplete neurotransmitters. In the left picture, prior to treatment, neurotransmitter levels are not high enough to prevent symptoms of disease. In the center picture, reuptake is blocked, neurotransmitters move from the vesicles of the pre-synaptic neuron to the synapse. In the right picture, the neurotransmitters are depleted, the increase in synaptic neurotransmitter levels results in an increase in MAO and COMT metabolism. Source of picture: The National Institute of Drug Abuse.
With regards to figure 2, the net effect of enzymatic metabolism is the depletion of neurotransmitter levels in the central nervous system.
Neurotransmitters do not cross the blood brain barrier. Therefore, the only way to increase central nervous system levels or to prevent the overall depletion of neurotransmitters when administering prescription drugs that block reuptake is to provide amino acid precursors, which are then synthesized into neurotransmitters. Administering L-tyrosine (not phenylalanine or n-acetyl-tyrosine) or L-dopa is the only way to predictably raise dopamine, norepinephrine, and epinephrine. Administering tryptophan or 5-hydroxytryptophan (5-HTP) is the only way to predictably raise serotonin levels in the central nervous system. It is noted that 5-HTP, L-dopa and tyrosine are available in the United States without a prescription. The ability of tryptophan to raise serotonin levels is limited because it is a rate-limited reaction.
The effects of neurotransmitter depletion by drugs may have far ranging implications. It has been found in studies that depletion of serotonin by drugs may also lead to a reduction the number of serotonin synapses in the hippocampus.43 This could indicate that in addition to depleting the overall amount of serotonin in the brain, it also leads to the destruction of the neuron itself over time.
More research is needed to determine the overall long term affect of taking these drugs. However, it is known that using amino acid therapy can reverse neurotransmitter depletion, regardless of the cause.
Coming up in this blog we will cover how neurotransmitters are produced from their amino acid precursors.
24. Effect of L-dopa administration on islet monoamine oxidase activity and glucose induced insulin release in the mouse. Pancreas. 1991 Sep; 6(5): 522-7 Lundquist, I : Panagiotidis, G : Stenstrom, A.
43. Serotonin and acetylcholine are crucial to maintain hippocampal synapses and memory acquisition in rats Neuroscience Letters 230 (1997) 13 16 Mutsumi Matsukawa, Megumu Ogawa, Kazuhiko Nakadate, Toru Maeshima, Yukio Ichitani, Nobufumi Kawai, Nobuo Okadoa.
