Monday, May 3, 2010

Dopamine - Serotonin's Secret Weapon

Following is a slightly edited extract from a lengthy article I published on mcmanweb three years ago ...

For two years running, dopamine has received my Newsletter’s coveted "Neurotransmitter of the Year" award. A review article in the March 2007 Archives of General Psychiatry by Boadie Dunlop MD and Charles Nemeroff MD, PhD, both of Emory University, makes a strong case for a three-peat:

Yes, serotonin is the neurotransmitter we tend to think of when it comes to depression, but, as the authors point out, a large number of animal studies, plus gene research and neuroimaging on humans and other findings "support the hypothesis that major depression is associated with a state of reduced dopamine transmission."

The research that led to the "monoamine hypothesis of depression" of the 1960s clearly fingered dopamine, along with serotonin and norepinephrine. But tricyclic antidepressants were hitting the scene at about the same time, all but assuring that dopamine would be overlooked. The later emergence of SSRIs meant that serotonin would grab all the attention. This despite the fact, as the authors point out:

"Most antidepressant treatments do not directly enhance dopamine neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure."

The authors go on to say that "anhedonia, the absolute or relative inability to experience pleasure, is one of two symptoms required for the diagnosis of major depression." Anhedonia is universally regarded as a "core" symptom of depression. It is well-established that dopamine plays a central role in the brain’s reward system, which includes inducing feelings of pleasure and positive mood states.

The authors cite a 2005 University of Toronto study of the brain scans of 24 subjects who were administered amphetamine. The subjects who were severely depressed had a hypersensitive response to the rewarding effects of the drug, and their scans revealed activation in the ventrolateral prefrontal and orbitofrontal cortices, and in two subcortical regions of the brain (the caudate and putamen).

As Dunlop and Nemeroff explain: "These findings further implicate dopamine circuit dysfunction in major depression."

In this context, the first generation of antidepressants may be the most modern. MAOIs prevent degradation of dopamine, as well as norepinephrine and serotonin. For individuals with atypical depression (leaden, fatigued, and lethargic describe some of the characteristics), MAOIs may represent an early treatment option rather than a late one.

The tricyclics that came out around the same time as MAOIs may also indirectly boost dopamine in the prefrontal cortex via their norepinephrine action.

Enter the new generation antidepressants such as SSRIs. Ironically, as the authors point out, when SSRIs work well it may be due to interactions between the serotonin system and the dopamine system. The authors cite a 1996 German study that found that those who responded to SSRIs - but not those who failed to respond - "exhibited increased dopamine binding to D2 receptors in the striatum and that the degree of increase in D2 binding correlated with improvement in Hamilton Depression Scale score."

In other words, dopamine may be serotonin’s secret weapon. It’s still way too soon to draw this conclusion, but we definitely have the basis for a strong hypothesis, not to mention "Neurotransmitter of the Year" distinctions for years to come.

Much more on dopamine on mcmanweb


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