Psycho-Babble Neurotransmitters Thread 883495

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Re: Do SSRI's cause dopamine depletion

Posted by Alexanderfromdenmark on April 6, 2009, at 3:06:33

In reply to Re: Do SSRI's cause dopamine depletion » Alexanderfromdenmark, posted by sowhysosad on April 5, 2009, at 16:39:40

> SSRI's also render D2 dopamine receptors supersensitive, which they think might contribute to the antidepressant effect.
>
> That said, so does CBT alone according to some other research, so maybe it's some healing mechanism of the brain as it recovers from depression.


Perhaps, depends on the SSRI of course. A drug like prozac has actually been shown to an "atypical" antidepressant in that it also inhibits reuptake of noradrenalin and dopamine.

My own experience with lexapro has been quite catastropic in that it just numbed me up, made me fatigued and apathectic, and has caused me secondary hypogonadism and lowered my thyroid hormone t3. Antidepressant my *ss.

 

Re: Do SSRI's cause dopamine depletion

Posted by sowhysosad on April 6, 2009, at 15:08:47

In reply to Re: Do SSRI's cause dopamine depletion, posted by Alexanderfromdenmark on April 6, 2009, at 3:06:33

> > SSRI's also render D2 dopamine receptors supersensitive, which they think might contribute to the antidepressant effect.
> >
> > That said, so does CBT alone according to some other research, so maybe it's some healing mechanism of the brain as it recovers from depression.
>
>
> Perhaps, depends on the SSRI of course. A drug like prozac has actually been shown to an "atypical" antidepressant in that it also inhibits reuptake of noradrenalin and dopamine.
>
> My own experience with lexapro has been quite catastropic in that it just numbed me up, made me fatigued and apathectic, and has caused me secondary hypogonadism and lowered my thyroid hormone t3. Antidepressant my *ss.
>

Pretty much all the SSRI's sensitise D2 receptors from what I've read, or at least fluoxetine, citalopram and paroxetine do:

http://www.ncbi.nlm.nih.gov/pubmed/15820269

As for fluoxetine and noradrenaline/dopamine, you're right in saying it increases levels of those neurotransmitters, at least in the prefrontal cortex. However, it doesn't significantly inhibit reuptake of catecholamines, so it must be doing it through some other mechanism.

 

Re: Do SSRI's cause dopamine depletion

Posted by Alexanderfromdenmark on April 8, 2009, at 17:28:11

In reply to Re: Do SSRI's cause dopamine depletion, posted by sowhysosad on April 6, 2009, at 15:08:47

> > > SSRI's also render D2 dopamine receptors supersensitive, which they think might contribute to the antidepressant effect.
> > >
> > > That said, so does CBT alone according to some other research, so maybe it's some healing mechanism of the brain as it recovers from depression.
> >
> >
> > Perhaps, depends on the SSRI of course. A drug like prozac has actually been shown to an "atypical" antidepressant in that it also inhibits reuptake of noradrenalin and dopamine.
> >
> > My own experience with lexapro has been quite catastropic in that it just numbed me up, made me fatigued and apathectic, and has caused me secondary hypogonadism and lowered my thyroid hormone t3. Antidepressant my *ss.
> >
>
> Pretty much all the SSRI's sensitise D2 receptors from what I've read, or at least fluoxetine, citalopram and paroxetine do:
>
> http://www.ncbi.nlm.nih.gov/pubmed/15820269
>
> As for fluoxetine and noradrenaline/dopamine, you're right in saying it increases levels of those neurotransmitters, at least in the prefrontal cortex. However, it doesn't significantly inhibit reuptake of catecholamines, so it must be doing it through some other mechanism.

But what is the significance of sensitizing d2 receptors? Generally I seem to find that studies show that ssri's downregulate dopamine, as such there is less dopamine and not more, sensitizing d2 receptors ot not.

on the subject on dopamine depletion take a look at this.

http://ajp.psychiatryonline.org/cgi/content/full/162/9/1755

 

Re: Do SSRI's cause dopamine depletion

Posted by sowhysosad on April 8, 2009, at 21:36:35

In reply to Re: Do SSRI's cause dopamine depletion, posted by Alexanderfromdenmark on April 8, 2009, at 17:28:11

> But what is the significance of sensitizing d2 receptors? Generally I seem to find that studies show that ssri's downregulate dopamine, as such there is less dopamine and not more, sensitizing d2 receptors ot not.
>
> on the subject on dopamine depletion take a look at this.
>
> http://ajp.psychiatryonline.org/cgi/content/full/162/9/1755

I'm not entirely sure what the significance is Alexander and the research is quite vague, just speculating that it "contributes to the antidepressant effect" in some way. I'd imagine it makes the brain more sensitive to the effects of what dopamine remains, and thus helps with energy, concentration and sleep regulation.

Interesting article about dopamine depletion. I've suffered some of those symptoms recently, which lends weight to my theory that my dopamine levels are low.

 

Re: Do SSRI's cause dopamine depletion

Posted by Amelia_in_StPaul on April 20, 2009, at 17:03:12

In reply to Re: Do SSRI's cause dopamine depletion » Alexanderfromdenmark, posted by sowhysosad on April 5, 2009, at 16:39:40

Not all of the SSRIs do the same thing. Fluoxetine has a different effect on dopamine than other SSRIs.

Fluoxetine as monotherapy in psychotic depression:
Report of 4 cases

(Excerpt) Recent studies demonstrate that serotonin exhibits a regulatory dopaminergic action by inhibiting the release of dopamine through 5-HT2A somatodendritic receptors in the surface of dopaminergic neurons; thus 5-HT2A antagonists (Altanserin) and 5-HT1A agonists (which may exert subtle inhibitory effects on dopaminergic cell bodies in the substantia nigra by means of autoreceptors ; Kelland, M.D. et al., 1990) or injury to the serotonergic tracts (Dray, A. et al., 1978), produce a disinhibition of dopaminergic neurons in the middle brain with modest increases in the release (Ennis, C. et al.,1981) and possibly in the synthesis of dopamine (Spampinato, U. et al., 1985) in the nucleus accumbens and the prefrontal cortex (Waldmeier, P.C. & Delini-Stula, A.A., 1979; Nedergaard, S. et al., 1988; Kelland, M.D. et al., 1990; Leysen, J.E. et al., 1994). On the other hand, some of the effects of the serotonin in the dopaminergic system can be mediated in indirect form through the modulation of the GABA and the cholinergic system (Dewey, S.L. et al., 1993). Fluoxetine and its active metabolite, norfluoxetine, have a serotonergic profile inhibiting serotonin reuptake the synaptic cleft (Lucas, R.A., 1992). However, the effect of the fluoxetine on other monoaminergic systems is not clearly established. Fluoxetine has been associated with the development of bradykinesia and rigidity, akathisia, shuffling gait, cogwheeling, tremor and akathisia, possibly by the activation of 5-HT2a receptors in dopaminergic neurons (Bouchard, R.H. et al., 1989; Lipinski, J.F. Jr. et al., 1989; Arya, D.K., 1994; Coulter, D.M. & Pillans, P.I., 1995) in a proportion similar to 1 out of 1000 individuals that consume SSRIs (Choo, V ., 1993). Fluoxetine, by increasing the serotonergic activity in the projections toward the substantia nigra from the dorsal raphe nuclei, can inhibit the firing rate of dopaminergic neurons, in such a way that the dopamine blockers in combination with fluoxetine can lead to extrapyramidal effects in patients even when they havent experienced adverse effects when treated only with antipsychotics (Levinson, M.L. et al., 1991). In spite of such findings, fluoxetine has relatively few side effects, especially when compared with the tricyclic antidepressants (Cooper, G.L., 1988) or with Amoxapine (Anton, R.F. & Burch, E.A., 1990).

Effects of fluoxetine on dopamine D2 receptors in the human brain: a positron emission tomography study

We have previously reported that repeated dosing with the selective serotonin reuptake inhibitor (SSRI) citalopram decreases striatal [11C]raclopride binding in healthy volunteers. As the SSRI-class antidepressant drugs are believed to have a similar mechanism of action, we wanted to explore whether the prototype SSRI drug, fluoxetine, shares the effects of citalopram on subcortical dopamine neurotransmission. Eight healthy male volunteers were studied using a randomized double-blind placebo-controlled study design. Striatal and thalamic D2-receptor binding was measured at baseline, after a single oral dose (20 mg) of fluoxetine, and after repeated dosing (2 wk, 20 mg/d). The D2-receptor binding potential (BP) was assessed using [11C]raclopride and 3D positron emission tomography. Repeated dosing of fluoxetine decreased BP in the right medial thalamus (p=0.022). Fluoxetine did not decrease striatal BP, but there was a trend (p=0.090) towards increased BP in the left putamen after repeated dosing. A single dose of fluoxetine did not affect BP in the thalamus or striatum. Fluoxetine appears to have a regionally selective effect on the dopaminergic neurotransmission in various areas of the brain. The current results after fluoxetine together with our previous data on citalopram suggest that the modulatory effects of these drugs on striatal dopaminergic neurotransmission are different upon repeated dosing and further substantiates pharmacological differences between SSRI-class drugs.

 

Re: Do SSRI's cause dopamine depletion

Posted by sowhysosad on April 21, 2009, at 7:08:07

In reply to Re: Do SSRI's cause dopamine depletion, posted by Amelia_in_StPaul on April 20, 2009, at 17:03:12

> Not all of the SSRIs do the same thing. Fluoxetine has a different effect on dopamine than other SSRIs.

...which would explain why many people find they're more motivated and energetic on fluoxetine than with other SSRI's ("activating" in the marketing spiel), and why it seems to work pretty well for atypical depression.

 

Re: Do SSRI's cause dopamine depletion

Posted by sowhysosad on April 21, 2009, at 7:26:14

In reply to Re: Do SSRI's cause dopamine depletion, posted by sowhysosad on April 21, 2009, at 7:08:07

Due to sleep deprivation and general stupidity I just posted without even reading the research, thinking it was this old chestnut:

Résumé / Abstract
Rationale: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. Objective: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. Methods: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. Results: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT2C receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. Conclusion: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.

I'm far too tired to get my head around that second piece of research that Amelia posted - is it contradicting other studies which say SSRI's reduce D2 receptor availability? Does the reduced binding potential mean the fluoxetine is acting as a D2 antagonist? I've also previously read that SSRI's supersensitise D2 receptors. My brain hurts...

 

Re: Do SSRI's cause dopamine depletion

Posted by Alexanderfromdenmark on April 26, 2009, at 17:43:58

In reply to Re: Do SSRI's cause dopamine depletion, posted by sowhysosad on April 21, 2009, at 7:26:14

> Due to sleep deprivation and general stupidity I just posted without even reading the research, thinking it was this old chestnut:
>
> Résumé / Abstract
> Rationale: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. Objective: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. Methods: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. Results: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT2C receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. Conclusion: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.
>
> I'm far too tired to get my head around that second piece of research that Amelia posted - is it contradicting other studies which say SSRI's reduce D2 receptor availability? Does the reduced binding potential mean the fluoxetine is acting as a D2 antagonist? I've also previously read that SSRI's supersensitise D2 receptors. My brain hurts...

I think all this far too complicated for us depressed brain foggers. Fx, the insomnia caused by the SSRI's could cause increased dopamine in the following day, because the brain is compensating for the lack of sleep. However I do feel that most SSRI side effects and things like hyperprolactima are definite pointers toward inhibition of dopamine.

 

Re: Do SSRI's cause dopamine depletion

Posted by Alexanderfromdenmark on April 26, 2009, at 17:48:50

In reply to Re: Do SSRI's cause dopamine depletion, posted by Alexanderfromdenmark on April 26, 2009, at 17:43:58

Also I think there's a difference between acute admnistration and long term adminitstration. Fx the brain in reponse to the huge increase in serotonin made say "F*ck man, lets pump out some dopamine to balance things out", so you get an increase dopamine, then you take an SSRI again and the brain again says "F*ck it man, keep that dopamine going, pump it up!", then after a period of weeks or months "The adujustment period", the brain just says"f*ck it, no more, we'll just get used to all that f*ck*ng serotonin and stop pumpting the dopamine" and that's when stuff like SSRI apathy, fatigue and PSSD complications set in.

 

Re: Do SSRI's cause dopamine depletion » Alexanderfromdenmark

Posted by sowhysosad on April 26, 2009, at 22:30:20

In reply to Re: Do SSRI's cause dopamine depletion, posted by Alexanderfromdenmark on April 26, 2009, at 17:48:50

> Also I think there's a difference between acute admnistration and long term adminitstration. Fx the brain in reponse to the huge increase in serotonin made say "F*ck man, lets pump out some dopamine to balance things out", so you get an increase dopamine, then you take an SSRI again and the brain again says "F*ck it man, keep that dopamine going, pump it up!", then after a period of weeks or months "The adujustment period", the brain just says"f*ck it, no more, we'll just get used to all that f*ck*ng serotonin and stop pumpting the dopamine" and that's when stuff like SSRI apathy, fatigue and PSSD complications set in.

You could be right. Weirdly though, SSRI's can also increase dopamine through other mechanisms. As I understand it, the dopamine reuptake pump starts to soak up some of that excess serotonin floating around, thus preventing reuptake of dopamine and leaving more in the synapse. Maybe that's how fluoxetine boosts dopamine in some parts of the brain?

After 3+ years on escitalopram followed by a lovely bout of sertraline-induced akathisia, it feels like I've been in a hypodopaminergic state for like 8 months now. All the symptoms seem to bear this out. Other AD's I've taken in the meantime seem to have somehow made it worse. As I mentioned elsewhere, NADH seems to be reversing the effect, thank f***.

 

Re: Do SSRI's cause dopamine depletion to d/r

Posted by Meltingpot on May 17, 2009, at 10:25:42

In reply to Re: Do SSRI's cause dopamine depletion, posted by desolationrower on March 4, 2009, at 20:54:14

Hi,

I thought wellbutrin acted more on norepinephrine thant on dopamine??

Denise

 

Re: Do SSRI's cause dopamine depletion to d/r

Posted by Alexanderfromdenmark on May 17, 2009, at 10:41:41

In reply to Re: Do SSRI's cause dopamine depletion to d/r, posted by Meltingpot on May 17, 2009, at 10:25:42

> Hi,
>
> I thought wellbutrin acted more on norepinephrine thant on dopamine??
>
> Denise


I think there are some conflicting views on that. Some sources say that wellbutrin equally inhibits NA and DA uptake, and some say it inhibits NA more than DA, and some DA more than NA. You might be right though. Why do you ask?

 

Re: Do SSRI's cause dopamine depletion to d/r

Posted by Meltingpot on May 17, 2009, at 11:19:12

In reply to Re: Do SSRI's cause dopamine depletion to d/r, posted by Alexanderfromdenmark on May 17, 2009, at 10:41:41

Hi,

That was a quick response :-) I ask because I tried Wellbutrin 350mg for two weeks and I felt nothing on it. I was thinking/hoping that perhaps this is because it does not act on dopamine so much as norepinephrine.

The reason I hoped this was the case was because at some point I would like to try a dopamine agonist but if Wellbutrin does act strongly on dopamine then this would increase my chances of not responding to a dopamine agonist.

Denise

 

Re: Do SSRI's cause dopamine depletion to d/r

Posted by Alexanderfromdenmark on May 17, 2009, at 11:39:47

In reply to Re: Do SSRI's cause dopamine depletion to d/r, posted by Meltingpot on May 17, 2009, at 11:19:12

> Hi,
>
> That was a quick response :-) I ask because I tried Wellbutrin 350mg for two weeks and I felt nothing on it. I was thinking/hoping that perhaps this is because it does not act on dopamine so much as norepinephrine.
>
> The reason I hoped this was the case was because at some point I would like to try a dopamine agonist but if Wellbutrin does act strongly on dopamine then this would increase my chances of not responding to a dopamine agonist.
>
> Denise


I don't think you should use Wellbutrin as your reference for a dopamine agonist. There's a lot of other definitive dopamine drugs out there.

 

Re: Do SSRI's cause dopamine depletion to d/r

Posted by garnet71 on May 17, 2009, at 16:32:03

In reply to Re: Do SSRI's cause dopamine depletion to d/r, posted by Meltingpot on May 17, 2009, at 11:19:12

The last time I tried Wellbutrin, it did not work at all for me; a few weeks later, I started taking dextro-amp which works much of the time....though I can't see it as a long term solution..However, I don't think Wellbutrin is comparable to other psychotropics-at least none I know of...

450 mg of WB worked best for me in the past....

Don't give up :-)

 

Re: Do SSRI's cause dopamine depletion » sowhysosad

Posted by Amelia_in_StPaul on May 18, 2009, at 23:30:16

In reply to Re: Do SSRI's cause dopamine depletion » Alexanderfromdenmark, posted by sowhysosad on April 26, 2009, at 22:30:20

I have cited studies that conclude exactly that (and specifically in regards to fluoxetine). Maybe in this thread? Anyway, yes, I believe that's what happens.

>, As I understand it, the dopamine reuptake pump starts to soak up some of that excess serotonin floating around, thus preventing reuptake of dopamine and leaving more in the synapse. Maybe that's how fluoxetine boosts dopamine in some parts of the brain?
>

 

Re: Do SSRI's cause dopamine depletion

Posted by desolationrower on May 19, 2009, at 0:44:55

In reply to Re: Do SSRI's cause dopamine depletion » sowhysosad, posted by Amelia_in_StPaul on May 18, 2009, at 23:30:16

yeah, studies different NA/DA effect of wellbutrin. and it might be an na releaser. or wrok by tnf-alpha inhibition. i don't think you can say its the same as pramiprexole or d-amp or desipramine.

-d/r

 

Re: Do SSRI's cause dopamine depletion » sowhysosad

Posted by SLS on May 20, 2009, at 5:44:34

In reply to Re: Do SSRI's cause dopamine depletion » Alexanderfromdenmark, posted by sowhysosad on April 26, 2009, at 22:30:20

> > Also I think there's a difference between acute admnistration and long term adminitstration. Fx the brain in reponse to the huge increase in serotonin made say "F*ck man, lets pump out some dopamine to balance things out", so you get an increase dopamine, then you take an SSRI again and the brain again says "F*ck it man, keep that dopamine going, pump it up!", then after a period of weeks or months "The adujustment period", the brain just says"f*ck it, no more, we'll just get used to all that f*ck*ng serotonin and stop pumpting the dopamine" and that's when stuff like SSRI apathy, fatigue and PSSD complications set in.
>
> You could be right. Weirdly though, SSRI's can also increase dopamine through other mechanisms. As I understand it, the dopamine reuptake pump starts to soak up some of that excess serotonin floating around, thus preventing reuptake of dopamine and leaving more in the synapse. Maybe that's how fluoxetine boosts dopamine in some parts of the brain?


Don't forget circuitry.

I think it has more to do with serotoninergic pathways modulating dopaminergic neurotransmission downstream. Perhaps there is a dysinhibition of dopamine activity as specific 5-HT receptors downregulate as a result of chronic exposure to SRI drugs like fluoxetine. Fluoxetine is a strange drug that is often considered to be an atypical SSRI. It does more than just inhibit the reuptake of serotonin.


- Scott


*********************************************

Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex
by
Bymaster FP, Zhang W, Carter PA,
Shaw J, Chernet E, Phebus L, Wong DT, Perry KW.
Neuroscience Research Division,
Lilly Research Laboratories,
Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
[email protected]
Psychopharmacology (Berl) 2002 Apr;160(4):353-61

ABSTRACT

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.

 

Re: Do SSRI's cause dopamine depletion » sowhysosad

Posted by SLS on May 20, 2009, at 5:46:21

In reply to Re: Do SSRI's cause dopamine depletion » Alexanderfromdenmark, posted by sowhysosad on April 26, 2009, at 22:30:20

> > Also I think there's a difference between acute admnistration and long term adminitstration. Fx the brain in reponse to the huge increase in serotonin made say "F*ck man, lets pump out some dopamine to balance things out", so you get an increase dopamine, then you take an SSRI again and the brain again says "F*ck it man, keep that dopamine going, pump it up!", then after a period of weeks or months "The adujustment period", the brain just says"f*ck it, no more, we'll just get used to all that f*ck*ng serotonin and stop pumpting the dopamine" and that's when stuff like SSRI apathy, fatigue and PSSD complications set in.
>
> You could be right. Weirdly though, SSRI's can also increase dopamine through other mechanisms. As I understand it, the dopamine reuptake pump starts to soak up some of that excess serotonin floating around, thus preventing reuptake of dopamine and leaving more in the synapse. Maybe that's how fluoxetine boosts dopamine in some parts of the brain?


Don't forget circuitry.

I think it has more to do with serotoninergic pathways modulating dopaminergic neurotransmission downstream. Perhaps there is a dysinhibition of dopamine activity as specific 5-HT receptors downregulate as a result of chronic exposure to SRI drugs like fluoxetine. Fluoxetine is a strange drug that is often considered to be an atypical SSRI. It does more than just inhibit the reuptake of serotonin.


- Scott


*********************************************

Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex
by
Bymaster FP, Zhang W, Carter PA,
Shaw J, Chernet E, Phebus L, Wong DT, Perry KW.
Neuroscience Research Division,
Lilly Research Laboratories,
Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
[email protected]
Psychopharmacology (Berl) 2002 Apr;160(4):353-61

ABSTRACT

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.

 

Re: Do SSRI's cause dopamine depletion » SLS

Posted by morganpmiller on June 5, 2009, at 23:17:28

In reply to Re: Do SSRI's cause dopamine depletion » sowhysosad, posted by SLS on May 20, 2009, at 5:46:21

Hi I'm new to this board. You guys know that Zoloft is a Serotonin and Dopamine reuptake inhibitor, especially at doses of 100 and more?

Re: Zoloft and dopamine reuptake inhibition

Posted by halcyondaze on January 19, 2007, at 21:44:16

In reply to Zoloft and dopamine reuptake inhibition, posted by Quintal on January 19, 2007, at 21:12:03

> I've been reading for a while that Zoloft is a mild dopamine reuptake inhibitor. Can anyone comment on how powerful a DA reuptake inhibitor it is with reference to others such as Ritalin, Wellbutrin etc.?
>
> Has anyone noticed important differences between Zoloft and other SSRIs that could be attributed to DA reuptake inhibition?
>
> My main memories from the last trial of this med were appalling nausea and vomiting with diarrhea and genital anaesthesia. Any similar?
>
> I'm attracted by the Zoloft packaging - I like the idea of his little smiley face looking out at me at every morning:
>
> http://upload.wikimedia.org/wikipedia/en/3/33/Zoloft_logo.png
>
> Q

It has far more dopamine reuptake inhibition than Wellbutrin. I have a chart from "Psychiatry Second Edition Therapeutics" by Wiley Publishing (editor: Alan Tasman) which is basically like a psychiatry Bible, with affinity (which equals 10^-7 x 1/Kd, where Kd equals the dissociation constant) and here are the numbers:

Serzone: approximately 0.3
Wellbutrin: approximately 0.2
Paxil: approximately 0.2
Zoloft: exactly 4.0
... with a bunch of the tricyclics and Prozac at less than 0.1.

It is amazing, if you see the chart. Zoloft is over four times more potent in terms of DA reuptake inhibition than any of the others.


Post #1


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I snagged these off the internet. Figured many would find these useful/interesting. I didn't take the pics, wish they were a little bit clearer.

<< http://i2.photobucket.com/albums/y32/tygereyes83/Book.jpg >>

1) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING MUSCARINIC RECEPTORS

<< http://i2.photobucket.com/albums/y32/tyger.../Muscarinic.jpg >>

2) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING HISTAMINIC RECEPTORS

<< http://i2.photobucket.com/albums/y32/tyger.../Histaminic.jpg >>

3) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING THE REUPTAKE OF NOREPINEPHRINE

<< http://i2.photobucket.com/albums/y32/tyger.../NEreuptake.jpg >>

4) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING ALPHA1ADRENORECEPTORS

<< http://i2.photobucket.com/albums/y32/tyger...lpha1adreno.jpg >>

5) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING THE REUPTAKE OF SEROTONIN

<< http://i2.photobucket.com/albums/y32/tyger...uptakeblock.jpg >>

6) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING 5HT-2A RECEPTORS

<< http://i2.photobucket.com/albums/y32/tyger...ceptorblock.jpg >>

7) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING THE REUPTAKE OF DOPAMINE

<< http://i2.photobucket.com/albums/y32/tyger...uptakeblock.jpg >>

8) RELATIVE AFFINITIES OF ANTIDEPRESSANTS FOR BLOCKING DOPAMINE RECEPTORS

<< http://i2.photobucket.com/albums/y32/tyger...ceptorblock.jpg >>

 

Re: Do SSRI's cause dopamine depletion

Posted by Brainbeard on July 28, 2009, at 14:39:27

In reply to Re: Do SSRI's cause dopamine depletion » SLS, posted by morganpmiller on June 5, 2009, at 23:17:28

> Hi I'm new to this board. You guys know that Zoloft is a Serotonin and Dopamine reuptake inhibitor, especially at doses of 100 and more?

> It has far more dopamine reuptake inhibition than Wellbutrin.

Yeah, but the gap between a drug's receptor affinities is what matters. Although sertraline's (Zoloft's) affinity for the dopamine reuptake pump is greater than that of bupropion (Wellbutrin), it is still 100 to 250 times smaller than sertraline's affinity for the serotonin reuptake pump. This means, as Dr. Preskorn argues, that 'the physician would have to increase the dose (ie, the concentration) of sertraline 100 times higher than that needed to inhibit the serotonin uptake pump before a comparable effect would be achieved on the dopamine uptake pump.' (Quoting from his online book: http://www.preskorn.com/books/ssri_s3.html)

Affinity ratios thus have to be seen 'within the context of the actual affinity of the drug for a secondary SOA [Site Of Action] relative to its affinity for its primary SOA and relative to the clinically relevant concentration needed to produce the desired clinical effect.'

Preskorn has also written a column with a subheading titled: 'Is sertraline an inhibitor of dopamine uptake?' Discussing this question, Preskorn concludes that 'it is quite doubtful that sertraline has any meaningful effect on dopamine uptake at concentrations typically achieved at its recommended dosing range, 50-200 mg/day.' (http://www.preskorn.com/columns/9909.html, scroll down)

Discussing other pharmacological data that support this view, he further concludes that 'While this does not absolutely rule out an effect of sertraline on dopamine uptake at concentrations usually achieved on its recommended dosing range, it places the burden of proof on the proponent of such a theory.'

Interestingly, Preskorn mentions a patient who used sertraline 300-400mg several times a day to achieve a stimulant high.

I do think that Preskorn underestimates the effects that even mild inhibition of the dopamine reuptake pump apparently has for many people. Alternatively, if Preskorn is entirely right, the stimulating effects of (higher doses of) Zoloft may be due to a different, yet unknown mechanism.
It is interesting that Zoloft is a derivative of tametraline, a norepinephrine and dopamine reuptake inhibitor. Quoting from the (excellent) Wikipedia article on sertraline (http://en.wikipedia.org/wiki/Sertraline):

'in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline.'

I like to think that this chemical origin might contribute to Zoloft's stimulant profile in some intangible way.

 

Re: Do SSRI's cause dopamine depletion

Posted by morganpmiller on July 30, 2009, at 22:45:35

In reply to Re: Do SSRI's cause dopamine depletion, posted by Brainbeard on July 28, 2009, at 14:39:27

Gotchya..I also think he underestimates the small effect of dopmamine reuptake inihibition. He's just one of those doctor's taking an extreme view and making a name for himself. Well, maybe not but it just seems many doctors do this, Dr. Peter Breggin being one of them.

 

Re: Do SSRI's cause dopamine depletion

Posted by Brainbeard on July 31, 2009, at 3:23:48

In reply to Re: Do SSRI's cause dopamine depletion, posted by morganpmiller on July 30, 2009, at 22:45:35

Yeah, Breggin has this complete tunnel vision that makes him such an unscientific whiner and a waste for the in itself noble cause of fighting Big Pharma.

 

Re: Do SSRI's cause dopamine depletion

Posted by SLS on July 31, 2009, at 7:01:57

In reply to Re: Do SSRI's cause dopamine depletion, posted by Brainbeard on July 31, 2009, at 3:23:48

> Yeah, Breggin has this complete tunnel vision that makes him such an unscientific whiner and a waste for the in itself noble cause of fighting Big Pharma.


Book sales and speaking engagements.


- Scott

 

Is there a way to naturally increase Dopamine?

Posted by Wanderer123 on August 30, 2009, at 19:15:06

In reply to Re: Do SSRI's cause dopamine depletion, posted by SLS on July 31, 2009, at 7:01:57

So Prozac has caused me apathy which I suspect is Dopamine-related. I don't know why but it became permanent. The question is, can I take some supplements and herbs to re-boost my Dopamine if its been damaged by an SSRI? Please help.


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