Posted by zeugma on February 20, 2006, at 13:02:52
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » zeugma, posted by SLS on February 20, 2006, at 9:34:00
> I think we are getting our cortical wires crossed.
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> :-)
>my cortical wires have fused :-) nonetheless I will try to follow your discussion (there is so much to learn, and so little I know)
> The point I was trying to make is that the dopamine found in the cortical areas we are talking about is not released into the synapses of NE neurons, but is mainly found just diffusing passively within the interstitial fluids (extracellularly), having been released by DA neurons elsewhere. It looks for any dopamine receptors it can find. This distant non-synaptic neurotransmission is sometimes called volume neurotransmission. It turns out that the NET is the only uptake pump in some areas able to clear this rogue dopamine. The rest is probably metabolized by catechol-o-methyltransferase (COMPT). Nevertheless, this diffused dopamine does affect the activity of these cortical areas and plays a role in regulating attention and working memory.>>
COMT pleomorphisms have been associated with ADHD, with response to modafinil, and with cognitive impairment in schizophrenia. All of this is presumably due to alterations in the volume transmission of dopamine in an area poor in DA transporters.
One theory is that NE uptake inhibitors, by prolonging the action of DA in the synapse, thereby increase the odds of its stimulating a DA receptor (mostly D1 and D4 receptors). It is the D4 receptor that has been the most highly associated with ADHD (in terms of allelic expression), except for the dopamine transporter itself (strong expression of the DA transporter is conjectured to reduce D4 stimulation in an area naturally low in DA transporters- my own conjecture- i.e. the DA transporter extends into areas normally cleared by the NE transporter, providing yet another mechanism for clearing extracellular DA, and thus reduces D4 stimulation by volume transmission of DA through the extracellular space- I was using 'synapse' perhaps wrongly as a synonym for this space). Overexpression of DA transporters, along with underexpression of D4 receptors, would conceivably cause additive effects and result in some of the more severe phenotypes of ADHD.
It is also worth noting that the dopamine beta hydroxylase enzyme, which converts DA into NE within the NE neuron (and thus after the NE transporter has sucked the DA into the neuron) has also been associated with ADHD, which would provide another reason NE transporter blockade is desirable in ADHD. One theory, based on an animal model, holds that ADHD is a hypernoradrenergic, hypodopaminergic state.
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> I guess the bottom line is that NE uptake inhibitors help to regulate the "tone" of dopaminergic neurons by sweeping up their mess for them. If the brooms break, the tone of DA neurons increases, leading them to become more easily stimulated by the messages they are meant to propogate.>>I think that NE uptake inhibitors have been investigated for the relief of 'negative symptoms' in schizophrenia, by stimulating the D4 receptors on the PFC, while not causing heightened stimulation of the D2 receptors in the accumbens that are responsible for the 'positive' symptoms.
In terms of ADHD, atomoxetine is considered more potent than placebo but weaker than methylphenidate or amphetamine. But it can be effective in those who have poorer responses to methylphenidate, at least, because overexpression of the DA transporter has been associated with MPH nonresponse (makes sense). In any case I have found atomoxetine to be the most 'stimulant-like' of the drugs I have taken.
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> To complicate the issue, not all of the DA taken up by NE terminals is deactivated. Some of it still manages to make its way into protective storage vesicles to be released with the next NE action potential.>>this is why the NE transporter has been called 'promiscuous.' it makes all of our lives more complicated
:-)
thank you for stimulating my thought (such that it can be)
-z
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> - Scott
poster:zeugma
thread:611154
URL: http://www.dr-bob.org/babble/20060219/msgs/611418.html