[Neuroscience] Re: SSRIs bind to post-synaptic 5-HT receptors and function as competitive antagonists?

John Hasenkam via neur-sci%40net.bio.net (by johnh from goawayplease.com)
Sat Jan 10 00:27:29 EST 2009

"Glen M. Sizemore" <gmsizemore2 from yahoo.com> wrote in message
news:4967d93e$0$24851$ed362ca5 from nr5c.newsreader.com...
> "John Hasenkam" <johnh from goawayplease.com> wrote in message
> news:0_ednaYTzJUf0vrUnZ2dnUVZ8srinZ2d from westnet.com.au...
>> 1. Recent controversy:
>> I've just finished reading Prozac Backlash(2000) by Glenmullen, a Harvard
>> based psychiatrist who claims SSRIs carry all sorts of risks. There are
>> some risks involved but generally quite slight, though the issue of Redux
>> is worrying. It was an SSRI for appetite suppression but was found to
>> destroy serotonergic axons.
> GS: I had not heard about this, but I only follow such topics when the
> need
> arises. Strange that an SSRI would kill 5-HT neurons...by
> hyperstimulation?

JH: Hyper stimulation is posited as a cause. However just a few days ago I
came across this:

J Neurochem. 1997 Nov;69(5):2096-101.

Serotonin acts as a radical scavenger and is oxidized to a dimer during the
respiratory burst of activated microglia.
Department of Psychiatry, University of Göttingen, Germany.
Serotonin (5-HT) is known to be readily oxidized and to act as a scavenger
of reactive oxygen species produced, e.g., in the presence of peroxidase and
H2O2 or during the respiratory burst of phagocytes. One major oxidation
product formed under these conditions, the 5-HT dimer
5,5'-dihydroxy-4,4'-bitryptamine (DHBT), was suggested to have neurotoxic
properties and to contribute to neuronal damage in neurodegenerative
disorders. It is shown in the present study that the luminol-enhanced
chemiluminescence signal measured after stimulation of the respiratory burst
activity of cultivated rat microglial cells by the addition of phorbol
12-myristate 13-acetate is suppressed by 5-HT in a dose-dependent manner.
During this process, 5-HT is oxidized to DHBT. Neither the intraventricular
injection of DHBT nor the addition of DHBT to cultured astrocytes, neurons,
or PC-12 cells was found to cause measurable cytotoxic effects. It is
concluded that extracellular 5-HT locally released from platelets and 5-HT
nerve endings at sites of brain damage or inflammation, through its
suppressant effect on the release of reactive oxygen species during the
respiratory burst of activated microglia, may contribute to attenuate
secondary tissue damage in the CNS.
PMID: 9349555 [PubMed - indexed for MEDLINE]

>>Interesting given the known neurotoxicity of Ecstasy and that it is a
>>strong serotonin agonist.
> GS: Well...X is an indirect agonist - it is an uptake inhibitor (I don't
> know its specificity for serotonin, dopamine, and norepinephrine), and it
> probably does a lot of the things that amphetamines do in terms of release
> ("leaking") of monoamines directly from the cell.  But there are a bunch
> of
> psychostimulatnts (other amphetamines included) that don't - as far as I
> know - lead to destruction of 5-HT neurons. Am I missing something? Are we
> on the same page here, John?

JH: Uptake inhibitor, the typical strategy. Not sure about serotonin but it
is known that MAOs which degrade dopamine create products which are
neurotoxic. Hence agents like selegiline can be neuroprotective because of
their inhibition of MAOs.  So it might be interesting to see what
degradation products arise from the reuptake of serotonin.

>>In addition recent studies on mice found that mice raised on prozac grow
>>displaying depressive like symptoms.
> GS: It is easy - too easy! - to come up with a story here. Downregulation
> of
> the "5-HT system" could occur in a number of ways in response to
> hyperstimulation. Then, there is the whole issue of evaluating the cogency
> and quality of the behavioral studies you reference (I assume that you are
> referring to behavior here...if not...never mind!).

That's the problem: too easy. Mencken:
"For every human problem, there is a neat, simple solution; and it is
always wrong"



Brain Res. 2000 Nov 17;883(2):205-15. Chronic fluoxetine administration to
juvenile rats prevents age-associated dendritic spine proliferation in
Norrholm SD, Ouimet CC.
Program in Neuroscience, Department of Psychology, Florida State University,
211 Biomedical Research Facility, Tallahassee, FL 32306-4340, USA.
The density of dendritic spines, the postsynaptic sites of most excitatory
synapses, increases during the first 2 postnatal months in rat hippocampus.
Significant alterations in hippocampal levels of serotonin and
norepinephrine impact synaptic development during this time period. In the
present study, dendritic spine density was studied in the hippocampus (CA1)
and dentate gyrus of juvenile rats acutely and chronically exposed to
antidepressant drugs that act on serotonin and norepinephrine. One group of
21-day-old rats was given a single injection of a serotonin specific
re-uptake inhibitor (fluoxetine or fluvoxamine), a norepinephrine-specific
re-uptake inhibitor (desipramine), or saline and killed after 24 h. A second
group of rats was injected daily, beginning on postnatal day (PN) 21, for 3
weeks. This group was further subdivided into rats that were killed 1 day or
21 days after the last injection. Golgi analysis showed that a single
injection of fluvoxamine produced a significant increase in dendritic spine
density in stratum radiatum of CA1 and in the dentate gyrus. Further, acute
treatment with all three antidepressants increased the total length of
secondary dendrites in CA1, with fluoxetine and desipramine increasing the
number of secondary dendrites as well. In fluoxetine-treated animals killed
on days 42 or 62 (1 or 21 days post-treatment, respectively), dendritic
spine density remained at levels present in CA1 at 21 days. These results
show that acute antidepressant treatment can impact dendritic length and
spine density, and raise the possibility that chronic fluoxetine treatment
arrests spine development into young adulthood.
PMID: 11074049 [PubMed - indexed for MEDLINE]
The above paper is interesting because a great many patients on SSRIs
develop tolerance. One hopes this tolerance is arising because of "neural
adjustments" rather than pathology.

I can't evaluate the behavioral studies Glen, lack the skills for that.

>>I think Glenmullen is way over the top but still have serious concerns
>>about the widespread use of SSRIs in children. I am not against
>>antidepressants, in fact I consider these drugs to be a great benefit, but
>>I have concerns about the excessive reliance on these drugs. Effexor can
>>induce serious withdrawal symptoms, I don't care what the authorities say
>>I've heard enough people describe their SSRI as a "security blanket" to
>>wonder if this is not a manifestation of dependency. In fact the general
>>advice now is that one should never abruptly stop taking these drugs
>>because of potential withdrawal problems. Whoops, that should read ...
>>because of a potential "antidepressant discontinuation syndrome". Ha!
> GS: I don't have much of an opinion on "whether or not anti-depressants
> actually work," but that does not mean that I am disinterested. The topic,
> quite frankly, overwhelms me. It overwhelms me because we are ultimately
> talking about complex human behavior and ALL of the conceptual issues that
> pertain when that is the subject matter under consideration. How much of
> what you read really appears to take these conceptual issues into
> consideration?   Anyway...I have stressed this issue before...but I'm just
> ramblin' here.

JH: The drugs work but then so does exercise, ECT ... . Finding a "final
common pathway" is the challenge for many but I suspect that this is an
error. There may be several final common pathways that can instantiate
depression. Good, you're overwhelmed. Anyone who looks at this closely and
isn't overwhelmed is either an idiot or a liar. Before my vision collapsed
several years ago I was putting a lot of work into this. Very depressing and
as the doctors advised me: you have a very complex neuro-ophthalamic
pathology so stop reading so much. Stuff ém, they were wrong.

I threw a lot of data at you to demonstrate the sheer complexity of this
matter. If you come at it piecemeal it won't make sense and never will. You
will need to establish a broad physiological framework and that takes lots
of work. That's why I mentioned the papers by Sapolsky and Horrobin. Been
there, done that, and it still don't make sense to me.

Behavior: There are too many conceptual mindfields. There is the problem
diagnosing depression, a lack of reliable biomarkers for depression, the
need to exclude subjects carrying an allele for the 5HT transporter which,
together with early childhood neglect and present stress, markedly increases
the risk of depression. Consideration should also be given to tryptophan
absorption and intake as it is a necessary precursor for serotonin
production. Even the levels of IDO, which diverts tryptophan metabolism
towards Ky. Acid instead of serotonin production, is important. For example,
think of "sickness behavior"". Immune cells release IDO as many bacteria
require serotonin. The downside is loss of serotonin production. At a guess
I suggest pro-inflammatory cytokines increase the expression of IDO. Don't
know if microglia express IDO.

>> What is now being discovered is that CBT\psychotherapy is not only just
>> as
>> effective in treating depression but appears to be much better at
>> preventing relapses. In fact SSRI's can only prevent relapses if one
>> stays
>> on the drugs, which might explain why so many patients are on these for
>> life. Additionally, even strategies like insight meditation, exercise,
>> and
>> dietary changes can be very helpful in dealing with depression. Even
>> vitamin D status may be of slight value because it inhibits
>> pro-inflammatory cytokine production. Then there is the Lancet study
>> which
>> found slight increases in serotonin levels from sunshine exposure, this
>> probably relating to the changes in the melatonin - serotonin balance. Mt
>> is produced from serotonin, Mt production is rapidly stopped by sunlight
>> exposure(amacrine cells in retina, circadians, all that jazz), and Mt can
>> induce drowsiness and fatigue. That brings us to circadians, loss of
>> circadian stability is an intrinsic stressor, you can see the increase in
>> pro-inflammatory cytokines and for some depressives the loss of circadian
>> stability and hence sleep patterns is the straw that makes one rush for a
>> pill. Not surprising, even short periods of sleep deprivation can
>> significantly enhance the production of pro-inflammatory cytokines and
>> this has serious implications not just for depression but for cancer,
>> dementia, cardiovascular disease and what else??? The most remarkable
>> result I have read on the circadian issue was in relation to airline
>> staff
>> who crossed timelines and experienced persistent circadian disruption but
>> without sleep deprivation. 5 year study found differences in temporal
>> lobe
>> volumes and cognitive scores.
> Yes...you are simultaneously raising conceptual issues as well as alleged
> (not meant pejoratively) complex cascades of biochemical variables. I've
> already implied that I don't have much to offer - but I am interested in
> what you are saying.

>> 2.
>> I'm also wondering if the "competitive antagonist" = inverse agonist.
>> These ligands bind the receptor, change its conformation, and thereby
>> prevent second messenger\adaptor proteins coming into play when a agonist
>> ligand attaches to the receptor.
> GS: I don't know what you are referring to when you say " "these ligands."
> The difference between "competitive antagonists" (CAnt) and "inverse
> agonist" (IA) in my, admittedly, amateurish  understanding, is that IAs
> reduce the basal level of spontaneous 2nd messanger stuff, as well as
> competing in the CAnt sense.

This might help(full paper freely available at the link):


Multiple Signaling States of G-Protein-Coupled Receptors
Abstract--Studies have been amassed in the past several years indicating
that an agonist can conform a receptor into an activation state that is
dependent upon an intrinsic property of the agonist usually based upon its
chemical composition. Theoretically, each different agonist could impart its
own unique activation state. Evidence for multiple signaling states for the
G-protein-coupled receptors will be reviewed and is derived from many
different pharmacological behaviors: efficacy, kinetics, protean agonism,
differential desensitization and internalization, inverse agonism, and
fusion chimeras. A recent extension of the ternary complex model is
suggested by evidence that the different processes that govern deactivation,
such as desensitization and internalization, is also regulated by conformers
specific to the agonist. Rhodopsin may serve as a primer for the study of
multiple activation states. Therapeutic implications that utilize multiple
signaling states hold vast promise in the rationale design of drugs.


Structural changes induced by the binding of agonists, antagonists, and
inverse agonists to the cloned -opioid receptor immobilized on a
solid-supported lipid bilayer were also investigated using plasmon-waveguide
resonance spectroscopy. Agonist binding causes an increase in membrane
thickness because of receptor elongation, a mass density increase due to an
influx of lipid molecules into the bilayer, and an increase in refractive
index anisotropy due to transmembrane helix and fatty acyl chain ordering.
In contrast, antagonist binding produces no measurable change in either
membrane thickness or mass density and a significantly larger increase in
refractive index anisotropy, the latter thought to be due to a greater
extent of helix and acyl chain ordering within the membrane interior. An
inverse agonist produces membrane thickness, mass density, and refractive
index anisotropy increases which are similar to, but considerably smaller
than, those generated by agonists


1. Native Systems. Interesting and novel ligands exist called "protean"
agonists. Proteus was a sea god in Greek mythology and the herdsman of
Poseidon's seals who had the ability to change his shape at will. Protean
agonists were predicted to exist from theoretical arguments based upon
multiple active conformations of GPCRs (Kenakin, 1997). It was predicted
that a protean agonist could act both as an agonist or an inverse agonist at
the same GPCR. To see this effect, one has to use receptors or tissues that
exhibit a high level of constitutive activity. The reversal from agonism to
inverse agonism would only occur when an agonist produces an active
conformation of lower efficacy than a totally active conformation.
Therefore, the higher the constitutive activity, the greater chance to see
this other conformation. Gbahou et al. (2003) showed that proxyfan, a
high-affinity histamine H3-receptor ligand, acted as a protean agonist at
recombinant H3 receptors expressed in the Chinese hamster ovary cells. Using
neurochemical and behavioral assays in rodents and cats, proxyfan displayed
a spectrum of activity ranging from full agonism to full inverse agonism.
Thus, protean agonism demonstrated the existence of alternative agonist
active states that was different from the constitutively active state in
this system. This was the first report of protean agonism existing for
native receptors under physiological conditions.

>>I haven't had time to look into this but the 5HT2c receptor appears to
>>activate production of arachidonic acid(need to find quantifiers for the
>>degree of production), a known pro-inflammatory mediator because it paves
>>the way for pge 2, which in turns helps maintain the expression of
>>pro-inflammatory cytokines(eg. il1, tnfa, il6 is tricky, can work both
>>ways). What is not that well known is that depression can involve
>>substantial increases in pro-inflammatory cytokines and it appears that
>>trying to understand depression by sole reference to the CNS is doomed to
>>fail. Keynote article: Cytokines and Depression: the need for a new
>>paradigm. I have this buried in my archives. We must consider endocrine
>>immunological impacts as well. In regard to this Sapolsky et al has a
>>review article, I need to read that again ... . The reason omega 3 intake
>>can help in depression, and possibly some other neuro disorders, is that
>>EPA inhibits A. acid production, diverting the pathways to
>>anti-inflammatory prostaglandins. What I have not looked into is how
>>serotonin impacts on immunological function, many immune cells have 5HT
>> For a very different perspective on these matters look up the ideas of
>> David Horrobin, I have a seminal article of his in my archives, that
>> would
>> be a good starting point. If you so wish, give me some time, I'll email
>> you some of these articles.
> GS: This is all beyond my understanding. You're claiming that SSRIs work
> via
> some very roundabout mechanisms? I can't say...more power to you John.

JH: I'm saying that there are multiple processes involved and I don't have a
clue as to how to make sense of it all. I don't doubt there will be direct
and indirect effects. Depression can arise through a number of avenues,
whether or not we can ever define depression within individuals by reference
to a specific physiological and neurological status is a question I can't
answer. That is, in any given individual we may define depression by a set
of states but we should not assume that the same physiological status will
result in depression in other individuals. Yeah, that seems odd.

The other issue here is that we must consider all the types of depression:

post partum(I'll take odds that relates to omega 3 stripping by the fetus
from the mother-does happen - and increase in IDO)
sickness behavior
5HT transporter induced
tryptophan depletion induced

>> PS: haven't looked too closely at depression for many years now so I'm
>> rusty. I have a small mountain of data in my archives though so if you
>> any
>> specific queries email me and I'll see what I can do to help.
>> Be well,
>> John.
> GS: Be well also, John. Trying to tackle so-called "psychiatric disorders"
> is a thankless task. I have talked about the conceptual problems that
> plague
> any discussion of complex human behavior, and you have alluded to
> potential
> biochemical issues that are independent of usual CNS considerations. And
> you
> have mentioned behavioral sorts of interventions. I simply don't have a
> strong opinion. I'm in an odd position...I think that our understanding of
> behavior (even in rats) is rudimentary, and any discussion of human
> "psychiatric disorders" is necessarily...errr...premature...yet...talk
> about
> them we must! Anyway...now I'm really rambling!  Oh! Dang! I was going to
> give you a reference concerning SSRIs and direct 5-HT effects...I brought
> the damn paper home but can't find it right now! Anyway...I'll  get it to
> you...

JH: Disgusting personal example. Because of my vision problem I was referred
to the Commonwealth Rehabilitation Service some years ago. The
"psychologist" there was convinced I had a psychopathology, insisted on a
psychiatric assessment. The two major problems the psychiatrist identified

"Of course there were the prejudices and biases that happened such that most
people on seeing his appearance would regard him as mentally deficient,
retarded and more likely to make unfavourable conclusions about his
personality and character, this of course is well accepted and well
substantiated in the literature. One only needs to look at the beauty and
cosmetic surgery industry to confirm society's preoccupation with youth and


When asked directly about his self-esteem he rejected the concept outright
and gave an academic argument and justification for his opinion, through
which one can see insight into his personality and intelligence. Therein
lies another aspect of this man's presentation and that is indeed his
personality. Without having formal testing I don't believe there is any
evidence to say that he has an organic personality problem, nevertheless he
is an unusual character. His appearance belies his higher intelligence and
indeed substantial knowledge base. I suspect at times he is able in his
words to 'play dumb' and then catch people out if not embarrass and
humiliate them with his intellectual prowess."


I will never forget the look on his face when I shot him down over the
self-esteem question. He didn't even bother to challenge me, probably
because he knew I was right and he felt a little foolish for asking a
question based on a spurious assumption(look up "Roy Baumeister"
http://www.fsu.edu/profiles/baumeister/). Incredibly, the psychiatrist was
quietly suggesting that the psychologist's opinion of me was potentially
driven by the types of discrimination people like myself are often victims
of. And yet, the "psychologist" then wanted another assessment because she
thought the first was in error. I wish more clinicians shared your cynicism.

I don't know why you consider your position "odd". Perhaps because of a
general lack of cynicism?

Cynicism is a euphemism for realism. Seeing things the way they really are,
instead of the way we'd like them to be.

*Hans Selye

For all this rambling, I haven't even addressed why SNRI's may be a better
strategy, particularly given that nore may inhibit microglial activation and
by increasing activity in the orbitofrontal cortices(particularly the right
as nore expression is higher in the right frontals) and these corticies are
believed to inhibit amygdala activity. There is the suggestion that in
depressives the right amygdala is larger than in norms.

I'm just throwing stuff at you Glen in the hope that it will give you some
idea of what you have let yourself in for. At an epistemological level you
have a very difficult choice: to focus solely on the neurobiology of
antidepressants or attempt to develop a broader perspective on the issue of
depression. If I may presume to be directive, I suggest you focus on the
former and play with the latter.

Congratulations, you made me open a long dormant database.

> G.

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