is one of the most important symptoms of depression. I wrote href="http://scienceblogs.com/corpuscallosum/2007/03/basic_concepts_anhedonia.php">a
post about it a while back, so I won’t go into the definition
in this post, other than to summarize by saying that it is the
inability to experience pleasure in response to activities or events
that otherwise would be pleasurable.
It is difficult to do studies on the brain mechanisms involved in the
genesis of individual symptoms. Progress has been made, but
it has been slow.
When I was in residency, toward the end of the last millennium, I
attended a lecture on neurophysiology. Unfortunately, I can’t
recall who was giving the lecture, but I do remember one slide that was
shown. After a long and complicated review of how
neurotransmitters are made and released, we saw this:
It was good for a laugh, even though it was not quite true.
We knew about second messengers; we even knew what some of
them were. But we had little inkling of what the second
messengers did, or how it all worked.
Now, this knowledge is being used in pharmaceutical development to
search for new molecular entities that may be useful in the treatment
In this search, we have to have some idea of
where to look.
The illustration shows the location of two sites in the
One, the href="http://en.wikipedia.org/wiki/Ventral_tegmental_area">ventral
tegmental area (VTA), is where href="http://en.wikipedia.org/wiki/Dopamine">dopamine
is produced. The other, the href="http://en.wikipedia.org/wiki/Nucleus_accumbens">nucleus
accumbens (NAcc), is one of the places that dopamine goes to
produce an effect.
Dopamine is a neurotransmitter that is known to be involved in
Therefore, it is sensible to look at locations where dopamine
is active, in order to find the location in the brain where hedonic
Writing for GlaxoSmithKline’s
Evoniuk describes how this is guiding drug development:
All currently marketed antidepressants are thought to work via
monoaminergic mechanisms. The two most prevalent mechanisms are the
blockade of serotonin, noradrenaline and/or dopamine reuptake (e.g.
SSRIs, SNRIs, NDRIs) or the inhibition of monoamine break-down in the
synaptic cleft via MAO inhibition. This led to the formulation of the
monoamine hypothesis of depression, which suggests that depression
arises from a deficiency in monoamine neurotransmission in brain areas
critical to the regulation of mood and other key symptoms of the
disorder. This theory continues to prevail, even in the absence of
clear evidence of monoamine deficits in the brain of depressed humans
or animals exhibiting depression-like behavior (Stahl SM. Essential
Psychopharmacology. 2nd ed.), and has led to validation of current
animal models of depression primarily on the basis of monoaminergic
mechanisms. Consequently, it is questionable whether these models would
be useful in identifying effective antidepressant drugs that work via
The latter point is a matter of great interest. The monoamine
mine has been worked over pretty well at this point, and nobody is
really satisfied with what it has gotten us. Dr. Evoniuk
points out that a few other pathways have been explored (substance P
antagonists, CRF antagonists, gonadal steroids), but without success.
So what happens in the nucleus accumbens, and is there anything in the
“something” that happens that could be a target for pharmaceutical
When dopamine binds to its receptors on the neurons in the NAcc,
“something happens” inside the neuron. The effect varies in
response to a number of variables. In particular, though,
dopamine is involved in regulating the level of phosphorylated cyclic
AMP response element binding protein (CREB). CREB is involved
in regulating DNA transcription in the nucleus of the neuron.
This affects the type and quantity of proteins that are
produced in the cell.
Evoniuk’s essay described the evidence supporting the hypothesis that
phosphorylated CREB levels play a role in the pathophysiology of
Engineered viruses have been developed which, when
selectively introduced into specific brain structures, turn CREB
phosphorylation either on or off. Thus a virus named pCREB elicits
overexpression of phosphorylated CREB) whereas the variant named mCREB
prevents normal CREB function in the brain regions where it is
introduced. This has allowed researchers to study the function of this
signaling molecule in awake, freely-moving animals using standard
The pCREB virus results in a chronic increase in the amount of
phosphorylated CREB. The (mutant) mCREB virus decreases
When phosphorylated CREB is increased in this way, the rodent test
subjects develop something that looks like anhedonia.
Although it would be premature to say that we understand
this, there are some clues. increased phosphorylated CREB
results in increased production of a class of endogenous peptide
It turns out that high levels of dynorphin lead, not to the euphoria
that some people get from opioids, but to apathy and loss of
Note that the methodology used in this research cannot be applied
directly to people. No one is going to suggest lowering
phosphorylated CREB by injecting mutant viruses into people’s brains.
However, the idea is that we might be able to find
a kinder, gentler way to produce the same effect, all without
directly modifying the transmission of monoamine neurotransmitters.