Posted by Larry Hoover on December 29, 2005, at 6:19:28
In reply to no begged Q's, hopefully, but impressionistic » Larry Hoover, posted by zeugma on December 28, 2005, at 21:10:18
> > C-fos signalling is so fundamental a response to receptor complex formation that it is perhaps the least discriminative of any possible marker for activation. This link gives some sense of what I mean: http://cellbio.med.harvard.edu/faculty/blenis/pdf/N_and_V_for_Murphy_et_al_Assoian.pdf
> >
> > The work in question, above, is very old. And I don't know what it shows us, other than we can localize some of the immediate chemical effects of psychoactive drugs. Until we can discriminate between different types of activation, I don't know that we gain much knowledge from this study, other than inferential with respect to how the brain is organized. And that presupposes that we understand the difference between acute and chronic drug exposure.
> >
> yes, but i am interested in acute effects, even though they do not result in mood elevation as such. the hypothesis of the authors of the old study was that the immediate effects are causally related to the later, AD ones. i realize this is a debatable assumption, but it bears investigation.I would very comfortably assume that the eventual drug effect (e.g. antidepressant) is indeed initiated by this acute exposure. I think that is an easy assumption, because c-fos is an "early immediate" gene. It is the primary "brain alerted, something changed" response. But, and it's a big but, the assumption that the effects of these initiations remain localized, is not a comfortable one for me. Following this "pebble dropping in a still pond" effect, rippling outwards, while more pebbles rain from the sky.....
> > > this is an update from this year:
> > >
> > > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15812568&query_hl=670&itool=pubmed_docsum
> > >
> > > -z
> >
> > I think the latter paper states much the same as I have suggested, that c-fos mapping is an investigative/screening type tool. By showing chemical activation of certain physical structures, a putative antidepressant molecule might be crudely assessed for activity, but we risk both types of hypothesis-testing error, yet. Stimulation of the selected brain complexes may not be unique to antidepressant activity, and antidepressant performance may be possible when such activation is absent.
> >
> Certainly. But the central nucleus of the amygdala is implicated in affective states. And if, for instance, atomoxetine did activate this structure, but was not an AD, this would bear investigation. granting that an assumption is made that such a structure is implicated, the question would be whether this structure was sufficient, or merely necessary, to elicit an AD effect. Perhaps atomoxetine's other effects, besides NE reuptake inhibition, somehow affect affective networks in a different way than desipramine, which it otherwise resembles pharmacologically- and perhaps also there is no common site of AD action , which would be a good thing to know, so as to rely more heavily on behavioral studies, or resign ourselves to the fact that AD's are about as good as they can get, since we have isolated mechanisms of AD action (monoaminergic neurotransmission) and perhaps others will turn up, but fortuitiously.Well, serotonin had its 15 minutes of fame, much extended by encores, and undeserved rave reviews. We move on to endorphins, and endocannabinoids (this kills me, how we name these receptors after drugs of abuse....it is so ....human), and cytokines, and yadda, yadda.
I don't know how many yaddas there are going to be, but I expect that simple list I started to eventually have many yaddas, if not many yaddas squared. ;-)
> > I'm very harsh in my analysis of this sort of research, because there is a significant risk of "begging the question", petitio principii. We may see patterns that don't exist, simply because we believe in the existence of the pattern itself.
> >
>
> it is better to be harsh with such research than to beg the question. the main research, in truth, i have done is on myself. from this i DO think that immediate effects of psychotropics bear on the outcome of the treatment.I agree. Now, how is it that some people (apparently, you and I) feel these immediate effects (why, we can even differentiate simultaneous immediate effects), whereas others note little or nothing, while going on to experience the main benefit of the drug? It boggles my mind, that population difference alone.
> hence i think the assumption of the authors of the study is a plausible one. and that c-fos however crude a marker is a place to start. but neither nortriptyline nor modafinil are beneficial in all depressions, and the fact that a drug activates a particular structure then is an interesting coincidence until the structure can be shown to play an integral role in mediating an AD response in *very* different brains (say, those who get an AD effect from bupropion, which i could not tolerate at all- strictly speaking then i should say that it was side effects that were too severe, not inefficacy.)
I think you just said the same thing I did, but in a different way. No, you spoke first, I read second. ;-)
> your reply was most gratifying to me.
That feels like one of the nicest compliments I've received in a long time. Thank you.
> i should comment again on this topc when i've read "Synaptic Self" again (he has done a lot of work on the amygdala-certainly there are worse ways to pass the time).
>
> -zI haven't the brain to read a book these days.....what might you say in review of this work?
Lar
poster:Larry Hoover
thread:590496
URL: http://www.dr-bob.org/babble/20051221/msgs/593055.html