![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 22 of 22. This is the beginning of the thread.
Posted by law663 on December 19, 2005, at 19:58:29
Can someone tell me what Fos-Immunoreactivity is?
Posted by Larry Hoover on December 20, 2005, at 1:48:41
In reply to what is Fos-Immunoreactivity?, posted by law663 on December 19, 2005, at 19:58:29
> Can someone tell me what Fos-Immunoreactivity is?
It is a method of determining neuronal activation. When a neuron is activated, it begins to express a protein the is the product of a gene called c-fos (fos for short). They have developed a substance that binds to that c-fos protein via an immune-like reaction. That complex can then be stained, so that it stands out from the background. The pattern of activated cells will thus be distinguishable from those not so activated. This is a process conducted on "sacrificed" creatures, i.e. post-mortem.
In a broader sense, this specific example you mentioned falls in the category of what is called immunohistochemical detection. They have immune primers for many different neuronal proteins, so depending on what the scientist is trying to find, they can use the appropriate immunoreactive binding agent, because those agents are both highly specific, and very efficient.
Back to your Fos-Immunoreactivity question. Somebody was trying to find a very general signal for neuronal activation, based on some manipulation they were doing. They could say, "substance X activated neurons of type y, in brain region Z", based on C-fos immunoreactive staining.
Lar
Posted by zeugma on December 24, 2005, at 18:43:15
In reply to Re: what is Fos-Immunoreactivity? » law663, posted by Larry Hoover on December 20, 2005, at 1:48:41
hi larry,
hope you're having a good holiday.
i dug up this trove on antidepressants and c-Fos:
http://www.pubmedcentral.gov/picrender.fcgi?artid=1188655&blobtype=pdf
apparently iprindole and nortriptyline are more selective in their neuronal activation effects than any of the miscellany of other AD's tested. perhaps you can help interpret the results' significance (if any), since the authors don't seem to know what to make of it.
this is an update from this year:
-z
Posted by linkadge on December 24, 2005, at 19:48:50
In reply to Re: what is Fos-Immunoreactivity? » Larry Hoover, posted by zeugma on December 24, 2005, at 18:43:15
Correct me if I'm wrong, but I was under the impression that intermediate-early gene activation was a topic of research pertaining to the propensity of a drug to be addictive.
Cocaine and the amphetamines increase cfos espression (BDNF too!)
Weren't they testing substances so called "cocaine vaccines" which inhibited cfos activation ?
Linkadge
Posted by zeugma on December 24, 2005, at 19:55:56
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 24, 2005, at 19:48:50
stimulants induce widespread c-Fos induction. The two AD's that induced the most widespread c-Fos by far were bupropion and tranylcypromine.
-z
Posted by linkadge on December 24, 2005, at 20:10:19
In reply to Re: what is Fos-Immunoreactivity? » linkadge, posted by zeugma on December 24, 2005, at 19:55:56
Interesting. I certainly found parnate pleasurable. It was fast acting in that sence.
Anyhow, do you know in what region, cfos activation is linked to addiction ?I am under the belief that there are longstanding deficiancies in neuronal placticity may occur after an antidepressant is withdrawn, like with addictive substances.
Linkadge
Posted by linkadge on December 24, 2005, at 20:26:03
In reply to Re: what is Fos-Immunoreactivity? » Larry Hoover, posted by zeugma on December 24, 2005, at 18:43:15
Is there evidence to suggest that cfos activity is actually impaired in depression ?
Linkadge
Posted by zeugma on December 25, 2005, at 15:25:41
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 24, 2005, at 20:26:03
not that I know of, c-fos only says where an activity is taking place, not what activity it might be. it is a consistent result that AD's induce c-fos in the central nucleus of the amygdala. it has also been believed that AD's might exert their effects through interactions with the opioid systems. mu opioid receptors are the dominant opiate type in the central nucleus of the amygdala:
1: Neuroscience. 2005;133(1):97-103. Related Articles, Links
Mu-opioid-mediated inhibition of glutamate synaptic transmission in rat central amygdala neurons.Zhu W, Pan ZZ.
Department of Anesthesiology, the University of Texas-MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
The central nucleus of the amygdala (CeA) plays an important role both in stimulus-reward learning for the reinforcing effects of drugs of abuse and in environmental condition-induced analgesia. Both of these two CeA functions involve the opioid system within the CeA. However, the pharmacological profiles of its opioid receptor system have not been fully studied and the synaptic actions of opioid receptors in the CeA are largely unknown. In this study with whole-cell voltage-clamp recordings in brain slices in vitro, we examined actions of opioid agonists on glutamate-mediated excitatory postsynaptic currents (EPSCs) in CeA neurons. Opioid peptide methionine-enkephalin (ME; 10 microM) produced a significant inhibition (38%) in the amplitude of evoked EPSCs, an action mimicked by the mu-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO; 1 microM, 44%). Both effects of ME and DAMGO were abolished by the mu receptor antagonist CTAP (1 microM), suggesting a mu receptor-mediated effect. Neither delta-opioid receptor agonist [D-Pen(2),D-Pen(5)]-enkephalin (1 microM) nor kappa-opioid receptor agonist U69593 (300 nM) had any effect on the glutamate EPSC. ME significantly increased the paired-pulse ratio of the evoked EPSCs and decreased the frequency of miniature EPSCs without altering the amplitude of miniature EPSCs. Furthermore, the mu-opioid inhibition of the EPSC was blocked by 4-aminopyridine (4AP; 100 microM), a voltage-dependent potassium channel blocker, and by phospholipase A(2) inhibitors AACOCF(3) (10 microM) and quinacrine (10 microM). These results indicate that only the mu-opioid receptor is functionally present on presynaptic glutamatergic terminals in normal CeA neurons, and its activation reduces the probability of glutamate release through a signaling pathway involving phospholipase A(2) and the presynaptic, 4AP-sensitive potassium channel. This study provides evidence for the presynaptic regulation of glutamate synaptic transmission by mu-opioid receptors in CeA neurons.>>
This one is especially interesting:
J Pharmacol Exp Ther. 2004 Sep;310(3):1020-6. Epub 2004 Apr 30. Related Articles, Links
Chronic antidepressant treatment causes a selective reduction of mu-opioid receptor binding and functional coupling to G Proteins in the amygdala of fawn-hooded rats.Chen F, Lawrence AJ.
Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. f.chen@hfi.unimelb.edu.au
We have previously documented that chronic alcohol consumption or alcohol withdrawal affects mu-opioid receptor density and receptor-mediated G protein coupling in Fawn-Hooded (FH) rat brain, especially in mesolimbic regions. FH rats demonstrate comorbid depression and high voluntary alcohol consumption; treatment with standard antidepressants improves both facets of this phenotype. Accordingly, we sought to examine whether mu-opioid receptor binding and the receptor-mediated functional coupling to G protein is affected by this drug treatment. Using quantitative autoradiography, binding of mu-opioid receptors labeled by [125I]FK33,824 (D-Ala2,N-Me-Phe4,Met(O)5-ol enkephalin) and the coupling between receptors and G proteins determined by agonist-stimulated guanosine 5'-O -(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding was mapped throughout brain sections of FH rats after 10-day treatment with vehicle, desipramine, or sertraline. Both desipramine and sertraline produced significant decreases of [125I]FK33,824 binding in many brain regions; 13 of 20 measured regions for desipramine and 16 of 20 measured regions for sertraline. The coupling efficiency of mu-opioid receptors to G proteins was determined by an increase of [35S]GTPgammaS binding induced by stimulation with the mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 microM). In contrast to the receptor binding profile, functional coupling of receptors to G proteins was only significantly reduced in the amygdala, whereas it remained unchanged in other regions compared with control. The present findings suggest that antidepressants regulate opioid systems; however, this occurs differentially, and region-specific alteration of functional coupling of mu-opioid receptors to G proteins in the amygdala suggests that opioid function within the amygdala may be modulated by antidepressants.
i believe that morphine withdrawal has been used as an animal model of depression. the negative affective consequences of morphine withdrawal activate c-fos in the central nucleus of the amygdala:1: Neuroscience. 2005;134(1):9-19. Related Articles, Links
Involvement of the bed nucleus of the stria terminalis activated by the central nucleus of the amygdala in the negative affective component of morphine withdrawal in rats.Nakagawa T, Yamamoto R, Fujio M, Suzuki Y, Minami M, Satoh M, Kaneko S.
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. tnakaga@pharm.kyoto-u.ac.jp
The central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST) are key structures of the extended amygdala, which is suggested to be involved in drug addiction and reward. We have previously reported that the Ce plays a crucial role in the negative affective component of morphine withdrawal. In the present study, we examined the involvement of the neural pathway between the Ce and the BST in the negative affective component of morphine withdrawal in rats. Rats were rendered morphine dependent by s.c. implantation of a 75-mg morphine pellet for 3 days, and morphine withdrawal was precipitated by an i.p. injection of naloxone (0.3 mg/kg). In the place-conditioning paradigm, discrete bilateral excitotoxic lesions of the Ce or the BST significantly reduced naloxone-precipitated morphine withdrawal-induced conditioned place aversion. On the other hand, they had little effect on morphine withdrawal-induced somatic signs. In an immunohistochemical study for c-Fos protein, naloxone-precipitated morphine withdrawal dramatically induced c-Fos-immunoreactive neurons in the capsular part of the Ce, and the lateral and medial divisions of the BST. Bilateral excitotoxic lesion of the Ce reduced the number of morphine withdrawal-induced c-Fos-immunoreactive neurons in the lateral and medial BST, with significant decreases in the posterior, ventral and juxtacapsular parts of lateral division, and anterior part of the medial division, but not in the ventral part of the medial division of the BST. On the other hand, bilateral excitotoxic lesion of the BST had no effect on such c-Fos induction within the capsular part, nor the ventral and medial divisions of the Ce. These results suggest that activation of the BST mediated through the neural pathway from the Ce contributes to the negative affective component of morphine withdrawal.
-z
Posted by Larry Hoover on December 27, 2005, at 11:42:03
In reply to Re: what is Fos-Immunoreactivity? » Larry Hoover, posted by zeugma on December 24, 2005, at 18:43:15
> hi larry,
>
> hope you're having a good holiday.Thanks. Same back at ya.
> i dug up this trove on antidepressants and c-Fos:
>
> http://www.pubmedcentral.gov/picrender.fcgi?artid=1188655&blobtype=pdf
>
> apparently iprindole and nortriptyline are more selective in their neuronal activation effects than any of the miscellany of other AD's tested. perhaps you can help interpret the results' significance (if any), since the authors don't seem to know what to make of it.Interpret? That's where I least like to step beyond the descriptive. In such a complex system, we do not know that an activated neuronal network represents even so much as an excitatory or an inhibitory complex. Let alone our fragmentary sense of how the pieces fit together. Or that the observed brains were not even primate.
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.
> 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
>
> -zI 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.
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.
Best,
Lar
Posted by linkadge on December 27, 2005, at 16:29:55
In reply to Re: what is Fos-Immunoreactivity? » zeugma, posted by Larry Hoover on December 27, 2005, at 11:42:03
This study suggests that lithium works by reducing certain patterns of c-fos activity.
http://www.nature.com/npp/journal/v16/n6/abs/1380561a.html
It doesn't mention however, the effect of lithium on c-fos in the amygdala.
Interestingly, the study mentions how stress itself, can activate c-fos in certain brain regions.
Linkadge
Posted by Larry Hoover on December 28, 2005, at 10:33:28
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 27, 2005, at 16:29:55
> This study suggests that lithium works by reducing certain patterns of c-fos activity.
>
> http://www.nature.com/npp/journal/v16/n6/abs/1380561a.html
>
> It doesn't mention however, the effect of lithium on c-fos in the amygdala.
>
> Interestingly, the study mentions how stress itself, can activate c-fos in certain brain regions.
>
>
> LinkadgeI'd like to focus on the difference between the studies you and zeugma have referenced.
In the two studies z referred to, the stimulus was the drug itself. Acute exposure to the drug was "noticed" by certain specific brain structures. The stimulus was beyond a certain intensity threshold, and c-fos proteins/RNA were produced.
The lithium study was of chronic lithium exposed brains, where the stimulus was some contrived stressor. The comparison (not lithium exposed) brains differed in how they "noticed" the stressor, when compared to lithium-exposed brains. The reduced responsivity in some regions could be interpreted as a protective effect (or something else....<shrug>) of the lithium. It's certainly a modulatory effect. The significance of these differences is not clear, but we may make certain inferences about the pattern of changes.
I'm sure that c-fos reactivity also differs under chronic antidepressant exposure, and so on.
Lar
Posted by linkadge on December 28, 2005, at 12:14:35
In reply to Re: what is Fos-Immunoreactivity? » linkadge, posted by Larry Hoover on December 28, 2005, at 10:33:28
I would be interested in the effect that lithium or antipsychotics could have on the effects of c-fos induced by antidepressants. So lithium has an attenuating effect on c-fos in certain situations. Is this of relavance to its mood stabalizing effect?
So parnate and bupropion seemed to consistantly increase c-fos in more areas of the brain than other antidepressants. Is this related to the propensity for these two drugs to resemble psychostimulants in certain paradigms? Would the addition of lithium or an antipsychotic reduce certain activation, would it preserve c-fos acivation in the amygdala?
I wonder if deltaFosB is affected by parnate or bupropion. A member of the fos family that generally takes longer to turn on, has been linked to certain substance's addictivness.
Linkadge
Posted by linkadge on December 28, 2005, at 12:16:22
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 28, 2005, at 12:14:35
Linkadge
Posted by linkadge on December 28, 2005, at 12:18:18
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 28, 2005, at 12:16:22
http://biopsychiatry.com/cocaine/index.htm
Linkadge
Posted by zeugma on December 28, 2005, at 21:10:18
In reply to Re: what is Fos-Immunoreactivity? » zeugma, posted by Larry Hoover on December 27, 2005, at 11:42:03
d c-Fos:
> >
> > http://www.pubmedcentral.gov/picrender.fcgi?artid=1188655&blobtype=pdf
> >
> > apparently iprindole and nortriptyline are more selective in their neuronal activation effects than any of the miscellany of other AD's tested. perhaps you can help interpret the results' significance (if any), since the authors don't seem to know what to make of it.
>
> Interpret? That's where I least like to step beyond the descriptive. In such a complex system, we do not know that an activated neuronal network represents even so much as an excitatory or an inhibitory complex. Let alone our fragmentary sense of how the pieces fit together. Or that the observed brains were not even primate. >>That the observed brains were not primate doesn't bother me, since I have to take it on faith that most of these studies are written by possessors of primate brains.
(Ok, I've gotten that bit of bile against drug researchers out of my system. I feel better now.)
The reason the c-fos study intrigued me was because many the drugs I've had the fortune to ingest did have effects that were immediate, more or less. And this often cut across 'class' lines, i.e., nortriptyline and modafinil had similar immediate effects in me, a marked slowing of thought processes that I *believe* constitutes an 'antidepressant' effect in me. While methylphenidate actually had a less marked immediate effect (of course dose could play a role here) but there was no slowing of thought processes involved. And the drug intensified depression, as did atomoxetine, a drug that improved focus markedly (like methyphenidate) but lacked this 'slowing' effect. Now much of the justification for atomoxetine's being an effective ADHD treatment, but not AD, hinged on its putative differential site of action (the prefrontal cortex is very fashionable now, and everything from Zyprexa to Wellbutrin 'preferentially increases dopamine in the prefrontal cortex.')
For the record, I believe atomoxetine is an AD, but not a good one because it has other effects that eventually negate its AD effect. But that is just my opinion.
>
> 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.
> > 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.> 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. 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.)
your reply was most gratifying to me. 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).
-z
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
Posted by Larry Hoover on December 29, 2005, at 7:11:27
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 28, 2005, at 12:14:35
> I would be interested in the effect that lithium or antipsychotics could have on the effects of c-fos induced by antidepressants. So lithium has an attenuating effect on c-fos in certain situations. Is this of relavance to its mood stabalizing effect?
Do you see how you move away from the descriptive, as soon as you start considering relevance? It is tempting, even rational, to start making these hypotheses, but the science doesn't give us that. The science is in the observations....the knowledge is limited to "we observed ...." (I'm an empiricist. And, I don't even want to consider what happens to "science" when "important discoveries" turn out to be faked data. Like hydro lines cause leukemia. Not.)
I've seen too many theories come and go. Infinitely many more hypotheories (hypotheses)....
Okay, maybe not infinite. ;-)
> So parnate and bupropion seemed to consistantly increase c-fos in more areas of the brain than other antidepressants. Is this related to the propensity for these two drugs to resemble psychostimulants in certain paradigms? Would the addition of lithium or an antipsychotic reduce certain activation, would it preserve c-fos acivation in the amygdala?
You're a thinker. That's for sure. ;-)
> I wonder if deltaFosB is affected by parnate or bupropion. A member of the fos family that generally takes longer to turn on, has been linked to certain substance's addictivness.
>
> LinkadgeAfter reading your linked reference to d-fosB, I'd have to assume so. It's related to long-term potentiation, which is how the brain stores experience.
We had a long discussion about possible long-term drug effects. I don't question long-term drug effects conceptually, as they are part of the individual's experience. If we had the means, we could isolate specific permanent biochemical and genetic changes induced by exposure to any specific drug. If we had the means, we could isolate specific permanent biochemical and genetic changes induced by emotion. If we had the means, we could isolate specific permanent and genetic changes induced by thought. I think we could, if we had the means. But we don't. And all of those (and many others) are changing simultaneously. Which is which?
I'm not even sure we are born as tabula rasa (clean slates). As a matter of fact, I'm certain we're not. Absolutely convinced of it. And then we add unique experience to that. How big is infinity squared?
My concern is not seeing the forest for the trees. Heck, we can't see the tree for the bark. Heck, we can't see the bark for the cellulose. We can't see the cellulose for....I'm mangling the metaphor because I want to emphasize that virtually every piece of data about the brain that we have is scale dependent. The brain is an organ in a body. The e.g. limbic system is complex in the brain. The e.g. amygdala is a structure in the limbic system. The corticomedial group is a division of the amygdala. The nucleus medialis is cell cluster in the corticomedial group. Blah blah neuron, receptor, neurotransmitter, blah, blah, methylation, blah.
And it's a moving target.
That changes as it moves, because it moves.
Thousands (millions??) (billions??) of changes per second, accumulating for years.
And we want to link these scale-dependent data to behaviour?
Cause and effect? We're lucky to get correlation. And we even argue about that.
Just putting it out there.
Lar
Posted by linkadge on December 29, 2005, at 10:39:38
In reply to Re: what is Fos-Immunoreactivity? » linkadge, posted by Larry Hoover on December 29, 2005, at 7:11:27
I'll be the first to admit I don't know anything about this topic. I'm really just brainstorming. I may ask some rather loose questions just to try and direct my thinking thats all.
Linkadge
Posted by Larry Hoover on December 29, 2005, at 12:01:54
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 29, 2005, at 10:39:38
> I'll be the first to admit I don't know anything about this topic. I'm really just brainstorming. I may ask some rather loose questions just to try and direct my thinking thats all.
>
> Linkadge
And you may trigger a response. Not a problem, over here. It's an excellent topic.Must have scared the original poster (law663) away, though.
Lar
Posted by law663 on December 30, 2005, at 17:17:30
In reply to Re: what is Fos-Immunoreactivity? » linkadge, posted by Larry Hoover on December 29, 2005, at 12:01:54
Nope, I've been silently listening. What strikes me about this discussion is how C-Fos is like so many fads that continue to get published despite their problems. For instance, P300 still gets pubs, despite being "associated" with just about everything, e.g., psychopathy, schizophenia, add.
I suppose our tools are just so primative.
BTW: Have you noticed that there are so few studies that examine the long term use (more than 6 months) of ADs?
> > I'll be the first to admit I don't know anything about this topic. I'm really just brainstorming. I may ask some rather loose questions just to try and direct my thinking thats all.
> >
> > Linkadge
>
>
> And you may trigger a response. Not a problem, over here. It's an excellent topic.
>
> Must have scared the original poster (law663) away, though.
>
> Lar
Posted by linkadge on December 30, 2005, at 20:31:41
In reply to Re: what is Fos-Immunoreactivity?, posted by law663 on December 30, 2005, at 17:17:30
I find that very disturbing to say the least.
Another thing I find disturbing is the lack of attention payed to the antidepressant poop-out phenomina.
Some doctors don't admit it exists. Some doctors blame it on other things. Some doctors boost the drug dose higher without comment.
I'd like to see more long term studies 2+ years.Sure a drug might be able to change the tide, but sustainablity is a key issue in depression.
Linkadge
Posted by zeugma on January 1, 2006, at 13:50:36
In reply to Re: what is Fos-Immunoreactivity?, posted by linkadge on December 30, 2005, at 20:31:41
Comments about LeDoux' book "Synaptic Self":
LeDoux' book draws attention to two main concepts or principles in neuroscience:
1)Hebb's "neurons that fire together, wire together" model of learning at the synaptic level;
2) Kandel and Spencer's injunction to study neuronal connections at the levels of the simplest systems possible. This made discovery of long-term potentiation possible, which had been predicted by Hebb many years before.
Since LeDoux is not very theoretically-minded, he is not able, in my opionion, to give an account of the implications of 1). For instance (and this is what I was primarily interested in as I read the bok), he points out that neuromodulators such as serotonin, acytylcholine, etc., significantly alter the synaptic connections between neurons, and notes that this is crucial in memory formation, but does not give this a proper emphasis in terms of its importance in acquisition of generally adaptive or maladaptive behaviors. So he devotes a great deal of time to explaining how long-term potentiation processes influence fear conditioning in rodents, but has little to say about how this might relate to human anxiety and mood disorders.This, however, is the abstract of a more recent work which focuses on the amygdala and its role in anxiety disorders:
It is currently believed that the acquisition of classically conditioned fear involves potentiation of conditioned thalamic inputs in the lateral amygdala (LA). In turn, LA cells would excite more neurons in the central nucleus (CE) that, via their projections to the brain stem and hypothalamus, evoke fear responses. However, LA neurons do not directly contact brain stem-projecting CE neurons. This is problematic because CE projections to the periaqueductal gray and pontine reticular formation are believed to generate conditioned freezing and fear-potentiated startle, respectively. Moreover, like LA, CE may receive direct thalamic inputs communicating information about the conditioned and unconditioned stimuli. Finally, recent evidence suggests that the CE itself may be a critical site of plasticity. This review attempts to reconcile the current model with these observations. We suggest that potentiated LA outputs disinhibit CE projection neurons via GABAergic intercalated neurons, thereby permitting associative plasticity in CE. Thus plasticity in both LA and CE would be necessary for acquisition of conditioned fear. This revised model also accounts for inhibition of conditioned fear after extinction.
http://jn.physiology.org/cgi/content/full/92/1/1
1: Neuroimage. 2004 Oct;23(2):483-99.
Since LeDoux implies, but does not expand upon, hints that the amygdala is importance in reward- and well as fear- driven processes, the following article is relevant:
For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion.
Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, Gross JJ.
Department of Psychology, Columbia University, 369 Schermerhorn Hall, New York, NY 10027, USA. ochsner@psych.columbia.edu
Functional neuroimaging studies examining the neural bases of the cognitive control of emotion have found increased prefrontal and decreased amygdala activation for the reduction or down-regulation of negative emotion. It is unknown, however, (1) whether the same neural systems underlie the enhancement or up-regulation of emotion, and (2) whether altering the nature of the regulatory strategy alters the neural systems mediating the regulation. To address these questions using functional magnetic resonance imaging (fMRI), participants up- and down-regulated negative emotion either by focusing internally on the self-relevance of aversive scenes or by focusing externally on alternative meanings for pictured actions and their situational contexts. Results indicated (1a) that both up- and down-regulating negative emotion recruited prefrontal and anterior cingulate regions implicated in cognitive control, (1b) that amygdala activation was modulated up or down in accord with the regulatory goal, and (1c) that up-regulation uniquely recruited regions of left rostromedial PFC implicated in the retrieval of emotion knowledge, whereas down-regulation uniquely recruited regions of right lateral and orbital PFC implicated in behavioral inhibition. Results also indicated that (2) self-focused regulation recruited medial prefrontal regions implicated in internally focused processing, whereas situation-focused regulation recruited lateral prefrontal regions implicated in externally focused processing. These data suggest that both common and distinct neural systems support various forms of reappraisal and that which particular prefrontal systems modulate the amygdala in different ways depends on the regulatory goal and strategy employed.
A proposed mechanism for how the amygdala could influence reward-driven processes is given here:
J Comp Neurol. 2005 Aug 29;489(3):349-71. Related Articles, Links
Afferent connections of the amygdalopiriform transition area in the rat.Santiago AC, Shammah-Lagnado SJ.
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo SP 05508-900, Brazil.
The amygdalopiriform transition area (APir) is often considered part of the lateral entorhinal cortex (Entl). However, in contrast to Entl, APir densely innervates the central extended amygdala (EAc) and does not project to the dentate gyrus. In order to gain a more comprehensive understanding of these territories, the afferent connections of APir were examined in the rat with retrograde (cholera toxin B subunit or FluoroGold) and anterograde tracers (Phaseolus vulgaris leucoagglutinin) and compared to those of the neighboring Entl. The results suggest that APir and Entl are interconnected and receive topographically organized hippocampal projections. Both are targeted by the olfactory bulb, the piriform, posterior agranular insular and perirhinal cortices, the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus. Most importantly, the data reveal that APir and Entl also have specific inputs and should be viewed as separate anatomical entities. The APir receives robust projections from structures affiliated with the EAc, including the anterior basomedial and posterior basolateral amygdaloid nuclei, the gustatory thalamic region, parasubthalamic nucleus, and parabrachial area. The Entl is a major recipient for amygdaloid projections from the medial part of the lateral nucleus and the caudomedial part of the basolateral nucleus. Moreover, the medial septum, subicular complex, nucleus reuniens, supramammillary region, and nucleus incertus, which are associated with the hippocampal system, preferentially innervate the Entl. These data underscore that APir processes olfactory and gustatory information and is tightly linked to EAc operations, suggesting that it may play a role in reward mechanisms, particularly in hedonic aspects of feeding.
-z
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