Science

Our Favorite Neurotransmitters

They've already changed your life. Now find out why.

Let’s skip the introduction and cut straight to the chase:

The three neurotransmitters we are most familiar with - serotonin, norepinephrine, and dopamine - are classified as monoamines according to their chemical makeup. The monoamine hypothesis holds that mood disorders are caused by a depletion in one or more of these neurotransmitters, which makes sense in a flat earth sort of way, with no reference to recent advances in genomics, neuroscience, and brain imaging. Nevertheless, no one is dismissing any of the big three, not to mention the mighty two (glutamate and GABA), and the unsung one (substance P).

The following is culled from Stephen Stahl MD’s "Essential Pharmacology of Depression and Bipolar Disorder," "Essential Pharmacology of Antipsychotics and Mood Stabilizers," and other sources:

The Big Three - Norepinephrine

Norepinephrine (also referred to as noradrenaline) is manufactured in the neuron by enzymes acting on the amino acid tyrosine, which convert it into L-DOPA, then to dopamine (more on dopamine in a minute). Some of the dopamine is then converted to norepinephrine, where it is stored in packages called synaptic vesicles. Just as norepinephrine is created by enzymes, it can also be destroyed by enzymes, such as MAO (which also destroys serotonin and dopamine). Hence the MAO inhibitors that represent the first family of antidepressants.

When the neuron is working right, it releases norepinephrine through alpha 2 autoreceptors into the synapse - the gap between two neurons - which attaches to alpha 1, alpha 2, and beta 1receptors on the neuron on the other side of the synapse. From there, a signal is sent into the cell that cues certain genes to switch on proteins governing all manner of activity.

Most of the norepinephrine action takes place in an area of the brainstem known as the locus coeruleus, which monitors external stimuli and our responses (such as fight or flight) and pain. Norepinephrine and the locus coeruleus are also believed to play a role in cognition, mood, emotions, movement, and blood pressure. Difficulty concentrating, fatigue, apathy, and depression are some of the things that can result from norepinephrine going AWOL.

After norepinephrine is released into the synapse and attaches to receptors on the postsynaptic neuron, the presynaptic neuron vacuums some of the remaining neurotransmitters through a reuptake pump (transporter) for future use. The tricyclic class of antidepressants bind to the receptors that act as reuptake pumps, thus keeping norepinephrine in circulation (they also bind in a similar fashion to serotonin receptors). Several of the newer antidepressants also work in a similar fashion, including Effexor and Cymbalta.

Norepinephrine release can be turned on or off when the alpha 2 autoreceptor is stimulated by norepinephrine. It has a similar effect on serotonin through binding to the presynaptic serotonin heteroreceptors. The antidepressant Remeron works by "cutting the brake cable" (in Dr Stahl’s words) when it blocks the norepinephrine alpha 2 autoreceptors, flooding norepinephrine into the synapse, as well as attaching to the serotonin heteroreceptors, turning on serotonin flow.

Since norepinephrine does not cross the blood-brain barrier, those seeking natural treatment must opt for its building blocks. Tyrosine, a precursor of both norepinephrine and dopamine, can act as an energizer, according to natural treatment advocates, and is available over the counter. Phenylalanine, a precursor, to tyrosine, is also an option.

The BIg Three - Serotonin

Serotonin (5HT) is synthesized in the neuron from the amino acid tryptophan, which is converted to 5HTP, then to serotonin. It is released into the synapse in a similar fashion to norepinephrine. Serotonin has some 17 different types and subtypes of receptors, which underscores its importance as a neurotransmitter. Two presynaptic receptors serve as both brakes and enhancers of serotonin release when blocked by serotonin or norepinephrine, while the postsynaptic receptors regulate the release of the serotonin signal into the neuron. Serotonin projects from the raphe nucleus in the brainstem to the basal ganglia, frontal cortex, hypothalamus and limbic system, and down the spinal cord. Serotonin is also found in the GI tract, thus implicating itself in a host of functions, from mood to anxiety to sleep (serotonin makes melatonin, which regulates sleep) to sexual response to food craving and (in)digestion.

As in the case of norepinephrine, a presynaptic transporter sucks up excess serotonin from the synapse in preparation for the next release of the neurotransmitter. Both the older tricyclic antidepressants and the newer SSRIs and dual action meds such as Effexor are believed to work by binding to this reuptake pump, thus keeping more serotonin in circulation. Were this completely true, however, antidepressants would have an immediate effect, instead of taking at least two weeks to start making an impression and another two to six weeks to achieve full clinical benefit.

One explanation is that blocking the transporters desensitizes the neuron in a way that dampens normal firing for four weeks. Another explanation is that antidepressants also work on intracellular processes downstream of the neurotransmitters (see article).

Because SSRIs attach themselves to all the postsynaptic receptors, a number of functions are disrupted, resulting in unwanted side effects such as sexual dysfunction and usually transitory anxiety and agitation (which can be less than transitory and highly pronounced for some people). The Holy Grail would be an SSRI that selectively left open some of these receptors. Paradoxically, one antidepressant, Serzone (now only available in generic form), works by blocking the 5HT2A receptor, which, when functioning normally, is thought to inhibit the 5HT1A receptor (ie Serzone indirectly switches the 5HT1A receptor on).

Since serotonin does not cross the blood-brain barrier, those seeking a natural serotonin solution must opt for its building blocks. Tryptophan, the precursor to serotonin, was removed from the US market in 1989 after a manufacturer produced a highly toxic contaminate. Note that tryptophan is not inherently toxic, and that the FDA’s ban may have had something to do with the entry of Prozac into the market around the same time. Tryptophan is still available by prescription. Less is more, with lower doses (one to three gm) more effective than higher doses. Taking the amino acid with carbohydrates helps in its absorption.

The intermediary between tryptophan and serotonin, 5HTP, is available without prescription. A 2000 Eli Lilly study found that Prozac significantly increased 5HTP levels. But for those thinking of simply taking 5HTP and cutting out Prozac as the middleman, the one 5HTP-depression study on the MedLine database found the supplement did not work for a single one of the 17 treatment-resistant patients taking 5HTP.

The Big Three - Dopamine

Dopamine is manufactured by L-DOPA, which in turn is produced from tyrosine. There are several dopamine pathways in the brain, the one most relevant to our purposes being the mesolimbic dopamine pathway, which projects from the midbrain to the nucleus accumbens, a part of the limbic system thought to be involved in pleasure as well as delusions, psychosis, and drug abuse. According to Julia Ross MA, author of The Mood Cure, caffeine is a pathetic attempt to make up for lack of dopamine.

Cocaine is notorious for enhancing dopamine production, while antipsychotics bind to dopamine D2 receptors and thus inhibit too much of a good thing. Unfortunately, antipsychotics don't just limit themselves to the D2 receptors in the mesolimbic dopamine pathway, leading to what Dr Stahl calls a "high cost of doing business," from dulled cognition to Parkinsonian tremors and tardive dyskinesia to hyperlactation. As well as preventing psychosis, antipsychotics are also first line treatment for mania.

The newer atypical antipsychotics such as Zyprexa are thought to have a better side effects profile thanks to their affinity for the serotonin 2A receptors, which set in motion a chain of events that results in looser binding of the dopamine receptors, allowing some dopamine to reach the neuron. This same blocking of the serotonin 2A receptors also produces an antidepressant effect. Eli Lilly has entered the market with a combination Zyprexa-Prozac med (Symbyax) that is thought to result in more dopamine and norepinephrine, and to a lesser extent serotonin, in the prefrontal cortex, which may turbocharge antidepressant performance.

The antidepressant Wellbutrin enhances both dopamine and norepinephrine in the synapse via that faithful old standby, reuptake blockade. A small study found the dopamine agonist (enhancer) Mirapex, an anti-Parkinson’s drug that works on the nigrostratial dopamine pathway (projecting from the substantia nigra of the brainstem to the basal ganglia or striatum), produced a significant response in depressed patients.

Tyrosine, the precursor to norepinephrine and dopamine, is favored by natural treatment proponents.

The Mighty Two

Glutamate and GABA represent the yin-yang of the neurotransmitters, Darryle Schoepp PhD of Eli Lilly explained in a session at the 2003 American Psychiatric Association annual meeting, both present in nearly all synaptic function all over the brain, with the former acting in an excitatory capacity and the latter in an inhibitory role. The mood stabilizers are thought to act on one or the other or both.

There are two types of glutamate receptors, ionotropic (iGluR), including NMDA, kainate, and AMPA receptors; and metabotropic (mGluR), which mediate numerous chemical actions. When the NMDA receptor is working right, glutamate and glycine bind to the receptor, which opens up its corresponding ion channel and permits calcium entry into the neuron. This in turn promotes intracellular signaling essential to plasticity and survival.

Husseini Manji MD, Chief of the Laboratory of Molecular Pathophysiology at the NIMH, at the same APA session, reported what can go wrong: In response to stress and mood episodes, glutamate reuptake in the synapse is compromised, resulting in increased calcium influx through the NMDA receptors and ion channels into the neuron and the activation of certain calcium-dependent enzymes that can result in cell atrophy and death. In some patients, Dr Manji observed, their mood disorder may be fundamentally atrophic rather than symptomatic.

In an article in the May 2003 Biological Psychiatry, Dr Manji et al listed a number of experimental drugs that target the NMDA receptors. One small study found that the anesthetic, ketamine, an “NMDA receptor antagonist,” resulted in rapid improvement in depressed patients. The anticonvulsant felbamate, and a drug used in Germany to treat memory loss, memantine, are also being investigated for treating depression.

Meanwhile, over at the AMPA receptors, which are tied to MAP kinase and other processes, “AMPA receptor potentiators” (ARPs) may modulate these receptors and enhance MAP kinase activation. Several compounds are being investigated.

The mood stabilizer, Lamictal, with demonstrated efficacy for bipolar depression, is an antiglutamate agent. A drug currently on the market to treat ALS, riluzole, inhibits glutamate. A pilot study at the NIMH is underway to investigate its antidepressant effects.

GABA is formed in the brain from glutamate, glucose, and glutamine, and binds to one of two receptors on the postsynaptic neuron. GABA A receptors regulate excitability and anxiety, panic, and stress, and are the targets of benzodiazepines such as Ativan, barbiturates, and alcohol. Depressed individuals have decreased GABA in their cerebral spinal fluid and plasma.

Gerard Sanacora MD, PhD of Yale has used magnetic resonance spectroscopy to measure GABA in the brain, finding that those with melancholic depression show low GABA concentrations in the occipital cortex, while the depletion is not as pronounced for those with atypical depression, indicating a diagnostic potential for subtypes of depression (March, 2003 American Journal of Psychiatry). Before and after scans of eight patients who had ECT found a doubling of GABA, and similar scans of patients on SSRIs showed a slow rise in GABA levels in nine of 11 of them.

Julia Ross of Mood Cure fame refers to GABA as "our natural valium," and recommends it to her clients for calming down. However, as this neurotransmitter does not easily cross the blood-brain barrier, you may wind up instead with very expensive urine.

The Unsung One

At the 2003 APA meeting, Alan Schatzberg MD of Stanford, Richard Hargreaves PhD of Merck, and A John Rush MD of the University of Texas Southwestern Medical Center staged a coming out party of sorts for substance P, which was supposed to be the target of a new class of antidepressants:

Substance P was discovered in 1931. Its role in pain and inflammation was identified in 1961, and in depression in 1988. As opposed to the three neurotransmitters we know best, which are monoamines, substance P is a peptide derived from two different types of amino acids, and is localized in brain regions controlling affective behavior.

Substance P is released in response to stress and binds preferentially to the neurokinin-1 (NK-1) receptors, resulting in mood and emotional changes. Mice genetically engineered with no NK-1 receptors have greater firing of the serotonin neurons. A similar effect was found when the mice were administered a substance P antagonist that binds highly selectively to the NK-1 receptors, thus blocking out substance P.

Merck began experimenting with MK-0869, which led to aprepitant (Emend), which was approved in April 2003 by the FDA for treating chemo-induced nausea and vomiting. A 1998 phase II trial of 213 depressed patients found a better than 50 percent response over six weeks for those on Emend, which beat 20 mg of Paxil by a small margin and the placebo by a much wider margin. Seventy-two percent of the Emend patients completed the trial vs 64 percent of those on Paxil. The drug was also as effective as Paxil in reducing anxiety. A 2001 trial of 700 mild to moderately depressed patients on different doses of Emend or 20 mg Prozac or a placebo, however, failed, with all the groups showing similar improvement. Phase III trials proved a disappointment, and in Aug 2003 manufacturer Merck withdrew the drug from FDA consideration.

Ah, the neurotransmitter of outrageous fortune ...

Published 2003, reviewed Feb 11, 2008