Posted by JohnX on February 15, 2001, at 10:48:13
In reply to Re: my Amisulpride efficacy hypothesis, posted by JohnX on February 15, 2001, at 9:14:37
Oh yeah,
forgot to mention according to the
paper bupropion's dopamine re-uptake
in vivo occurs at doses 7x the dose
required for anti-depressant effect.
The 7x dose is also when there is
significant suppression of A9 and A10
neurons.So, its unclear to me. But it seems as
though Wellbutrin's main mode of action
is through noradrenergic reuptake coupled
with a decrease in tyrosine hydroxylase (limiting
factor in dopamine and noradrenaline synthesis).
The tyrosine hydroxylase depletion would cause
a dopamine depletion in the areas where
tyrosine hydroxylase is reduced. I presume this
would cause sensitization of the dopamine neurons,
since their really is no dopamine reuptake.
Whereas for noradrenergic neurons, the reuptake
may wash out the tyrosine hydroxylase reduction.
Perhaps this is also why beta-down regulation is not observed. Don't forget the locus ceruleus
does contain dopaminergic neurons.-John
> >
> >
> > I considered this over my Cap'n Crunch this morning:
> > Given the two states of dopamine transmission: Basal and Pulsatile, how does amisulpride effect such transmission. When should it work and when should it not work.
> >
> >
> > I tried amisulpride 10mg/day for a month, and noticed no subjective mitigation of symptoms.
> >
> > I have just started wellbutrin sr 150mg/day. My idea is this:
> >
> > Pulsatile, or hyperpolarization-modulated DA exocytosis is believed to be regulated by presynaptic Auto-Receptors, which Amisulpride is believed to act upon.
> >
> > My hypothesis is this: Basal, or "backround" levels of DA are regulated by the amount of DA transport in the synapse. Therefore, such an inverse relationship can be stated:
> >
> > 1
> > _______________________ = level of DA transport
> >
> > Efficacy of Amisulpride
> >
> > Moreover, it is possible that Wellbutrin modulates basal level of DA, and, therefore the workings of DA transport.
> >
> > Indeed, Wellbutrin is anything but immutable, sometimes making things worse, and sometimes better. Wellbutrin blocks Dopamine (DA) *reuptake*, while, at the same time *decreasing* release.
> >
> > Obviously, I have conducted no formal trial of such a hypothesis, however, these phenomenon may support it:
> >
> > 1.) Greater success of Amisulpride in Wellbutrin-resistant patients.
> >
> > 2.) Less success of Amisulpride in those who recently built a tolerance to psycho-stimulants.
> >
> > 3.) Less signficant success, or failure, of amisulpride in Wellbutrin-successful patients.
> >
> > Not sure, but any comments would be welcome. I should know in a few weeks if the wellbutrin works for me where Adderall has gradually failed.
> >
> > Elvis has left the building,
> >
> > -James
>
> James/Andrew,
>
> I prefer Lucky Charms , but anyways....
>
> Heres my *long* analysis to date, I'm currently
> trying to look into fields that Andrew is more
> familiar with to also understand Amisulpride and
> my other data points. I'm no expert, I design chips
> not brains, but I prefer to use deductive logic
> to tailor my medication instead of throwing darts.
>
> I have been trying to correlate my responses to
> Wellbutrin, Zoloft, Adderall (stand-alone), Adderall + Klonopin.
> Later, I'll have some Amisulpride data.
>
> I have been trying to understand the mechanism of action of Wellbutrin
> since it was one of the anti-depressants that I got a response from.
> The other was Zoloft. I tend to be very sensitive to chemicals.
> Sometimes I can induce a manic state, but it always is preceded
> by chemical injestion. I think this "technically" rules me out as bipolar,
> but whatever.
>
> Anyways, when I get a response, usually I have a short lived (hypo)manic episode
> followed by an irratic transition to a state of complete emotional numbing with
> massive muscle contraction facial pain. I talked about this with Andrew, and I
> kinda described it as a ping pong from positive psychosis to negative psychosis.
> The muscle contraction and loss of emotion is likely an indicator of a
> hypo-dopaminergic prefrontal cortex (this is where the neurons for the facial muscles are).
>
> Zoloft:
>
> Zoloft would knock out my emotions and cause facial pain after ~3 days
> pre anti-depressant response and then after about 7 days, the anti-depressant would
> kick for a short while, my emotions would return and the pain goes away, and then
> I would switch back to the bizarre loss of affect and facial pain. I read a paper
> regarding Zoloft's tendency to induce contraction headaches.
> The hypothesis was that sorotonin neurons innervating the VTA modulate
> the firing rate of the VTA dopamine neurons into the mPFC.
> Purportedly, 5ht-1 inputs increase the firing and 5ht-2 slow the firing.
> So, the paper suspected that Zoloft banging on 5ht-2 (until down-regulation?)
> decreased the firing rate of the VTA dopamine neurons causing the problem.
> I read another abstract stating that SSRIs can slightly reduce the
> basal firing of VTA neurons. I guess if you are more sensitive, then
> it can *greatly* reduce the firing rate?
>
> Adderall:
>
> I also have been trying to understand why I get quick poop-out (~3 days)
> when I take Aderrall stand-alone. When Aderall works, it
> alleviates my facial pain, but this could be unrelated to the VTA since
> it will increase dopamine elsewhere. I just read the latest and greatest
> paper which shows that amphetamine sensitization starts with amphetamine
> induced *serotonin* release in the VTA (A10), which in turn *decreases*
> NMDA glutamate release and long-term (short term for me) triggers a down stream
> sensitization. I found another abstract that claims 5ht2 antagonists reverse
> amphetamine induced slowing of A10 dopamine neuronal firing. How do the
> 5ht-2 receptors control serotonin release? If they are down-regulated
> by an anti-depressant, would this reduce serotonin release and evoke
> more burst like firing in the VTA ? The amphetamine paper also punched the dopamine
> receptors D1 and D2 with agonists/antagonists. It found that they could
> not suppress the amphetamine reduction of glutamate transmission. However
> Sulpride, a D2 antagonis,did reduce net amphetamine evoked dopamine
> transmission. Any thoughts? We suspect NMDA-partial agonists
> would prevent sensitization (so does Klonopin, I'm trying to find out why).
>
> Wellbutrin:
>
> Anyways, I read another paper on Wellbutrin which tries to theorize its
> mode of action and who would be non responders. Here is my Wellbutrin
> response: until the anti-depressant kicks in, it doesnt affect me at all,
> when it kicks in , it pulls a Zoloft. The difference is that it doesn't zap
> my emotions pre-response. The paper indicates that Wellbutrin reduces
> whole body norepinephrine turnover (explain please?). Responders showed
> no changes in plasma HVA (explain please?). Non-responders sowed a small
> increase. It also hypothesized that the metabolite hydroxy-buproprion was
> paying most of the bill via blockade of norepinephrine reuptake & decreased
> tyrosine hydroxylase immunoreactivity.
> Thus this would reduce monoamine production in some areas of the brain
> both for dopamine and norepinephrine but increase re-uptake.
> Perhaps this explains why it can reduce release of dopamine,
> and sensitize the dopamine neurons (who wins?).
> At dosed needed for an anti-depressant response, raphe serotonergic
> firing rates are not affected, nor are firing rates of A9,A10 neurons.
> At toxic doses, the firing rate of A10 neurons is slowed to a crawl
> (doesn't explain why). I suspect in my case that I am not hitting
> toxic doses, but some feedback after the response causes a substantial
> reduction in A10 firing - thus the numbing and facial pain.
>
> Any thoughts?
> What would Amisulpride do?
>
> -John
poster:JohnX
thread:53790
URL: http://www.dr-bob.org/babble/20010212/msgs/54059.html