Our Neurotransmitters - It's All About Signaling and Circuits

Patient Expert

Let's review what we know about neurotransmitters. First, we need to clear up a major myth:

It is tempting to conceive of neurotransmitters as complicit in some kind of a "chemical imbalance in the brain" conspiracy. Instead, it is more helpful to view them as signaling agents in our neural circuitry.

Our circuitry connects the disparate parts of the brain into a working whole. A breakdown in the circuitry can have profound effects. These breakdowns typically have to do with the strength or weakness of the signaling.

Some of the key neurotransmitters involved in mood:


Dopamine is implicated in depression, bipolar, schizophrenia, psychosis, Parkinson's, ADHD, addiction, and aggressive behavior.

Dopamine-producing neurons are located near the brainstem, and extend out through various circuits to stimulate specific cortical and subcortical structures. One pathway - the nigrostriatal - involves movement and cognition. Another - the mesocortical - is vital to concentration and executive function. Still another - the mesolimbic - is involved in motivation and the experience of pleasure and reward.

ADD meds and Parkinson's meds enhance dopamine production, street drugs such as cocaine spectacularly so. MAO-I antidepressants and buproprion have a much weaker effect. SSRI antidepressants may have an even weaker downstream effect.

Antipsychotics block dopamine D2 receptors, which has the effect of shutting down a lot of the excess noise in the brain. Unfortunately, these meds may also shut down cognition, motor control, and the experience of pleasure, resulting in a very high cost of doing business.


The advent of SSRI antidepressants focused attention on serotonin as the lead player in the "chemical imbalance" myth, as if a deficit of this neurotransmitter were the only cause of depression.

Actually, if you had to finger a single culprit, dopamine would be a far better candidate.

What we do know is that lack of serotonin leads to obsessive thoughts which is why the very first SSRI, Luvox, was indicated for OCD. Obsessive thinking can also feed into depression and anxiety. This may explain why - for some people - an SSRI makes an effective antidepressant or antianxiety med.

There are other reasons to account for the efficacy of an SSRI, but the science is far from definitive.

In the brain, serotonin neurons are located in the raphe nucleus of the brainstem and project throughout the brain. Serotonin is also found in the gut.

Serotonin is implicated in a host of functions, from mood to digestion to sexual craving to sleep. Predictably, the cost of treating depression with an SSRI may be sexual dysfunction and other effects.

Ecstasy and LSD are serotonin drugs of abuse.


Norepinephrine neurons are located mainly in the locus coeruleus in the brainstem and radiate throughout the brain. Among other things, the neurotransmitter plays a role in arousal, cognition, and emotions. Too little norepinephrine may account for psychomotor retardation in depression. Too much may result in anxiety.

The old tricyclic antidepressants (such as imipramine) and the newer SNRIs (such as Cymbalta) have dual serotonin-norepinephrine action.

GABA and Glutamate

These neurotransmitters represent the yin and yang of neural equilibrium, with both present throughout all areas of the brain. GABA is a modulatory neurotransmitter, with the effect of slowing down neural activity. Both alcohol and antianxiety meds target GABA receptors. A deficiency in GABA may account for melancholic depression.

Glutamate is an excitatory transmitter that stimulates neural activity. Too much glutamate may be a byproduct of the stress response, which can induce neurotoxic effects.

GABA-glutamate disregulation has been fingered in both bipolar and schizophrenia. Mood stabilizers are believed to target both these neurotransmitters.

Other Neurotransmitter Systems

Acetylcholine - Damage to this system has been linked to Alzheimer's, and possibly to depression. Cholinesterase inhibitors such as Aricept are believed to work by preventing the breakdown of acetylcholine.

Oxytocin and Vasopressin - Commonly referred to as the "love hormones," oxytocin plays a critical "feel good" role associated with falling in love while vasopressin is crucial to long-term pair-bonding. The real picture is far more complex, but - you get the picture.

Opioids - Endorphins are a popular term to describe complex chemical activity involved in killing pain, inducing sleep, and creating sensations of pleasure. Heroin, morphine, codeine, and oxycodone mimic endorphin activity by binding to opiate receptors.

Adenosine - Caffeine binds to these receptors, thus blocking fatigue-inducing adenosine neurotransmitters. A downstream effect of caffeine is mild dopamine release.

Hypocretins - Also called orexins, these neurotransmitters have recently been identified in sleep regulation. The novel wakefulness agents Provigil and Nuvigil are believed to act on hypocretins.

Endocannabinoids - The endocannabinoid system plays a major role in maintaining homeostasis in the body and the brain. As opposed to other neurotransmitters, which flow from the presynaptic neuron to the postsynaptic neuron, endocannabinoids travel backward, from "post" to "pre."

The effect is to dampen the flow of incoming neurotransmitter traffic, such as the excitatory neurotransmitter glutamate. This particular modulatory action may account for the calming (or doping) effects of the cannabinoids found in marijuana.


Again, it pays to think of neurotransmitters as signaling agents in our neural circuitry. Our meds (and alternative treatments) amount to an extremely clumsy attempt to enhance or dampen signaling, unfortunately with no regard to circuitry.

We may hit the right neurotransmitter, but in the wrong circuit. We may reduce the symptoms of our illness, but wind up feeling much worse and far less capable of coping with life's challenges.

It's as if we were to treat a broken finger by putting the whole hand in a cast, and then telling the patient he has to wear the cast the rest of his life.

Such are the consequences of viewing mental illness as a "chemical imbalance."