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Thu Jul 27 16:35:27 EST 2000

In article <miKf5.3916$R43.968614 at typhoon-news1.southeast.rr.com>, 
"Glen M. Sizemore" <gmsizemore at triad.rr.com> wrote:

> Hi all,
>  I'm an experimental psychologist (i.e., not a "brain guy")
> who has become interested in the neurobiology of drug self-
> administration. My questions concern 6-hydroxydopamine. My
> understanding is that 6-OHDA is taken up pre-synaptically via re-
> uptake mechanisms and kills those neurons. Thus, when one
> administers 6-OHDA into discrete brain areas, it kills neurons that
> project to those areas, but does not, at least directly, kill neurons
> whose cell bodies are IN that area. Is this correct? Another
> question is this: Where on neurons is 6-OHDA taken in? I assumed
> that it was only near the terminal buttons. If one puts a little 6-
> OHDA into, for example, the medial forebrain bundle, is it possible
> to kill a bunch of neurons in widely dispersed brain areas? I'm
> assuming that most of the MFB consists of axons. Finally, when
> one reads that content of DA in an excised brain area is such-and-
> such, what is being measured? Would extracellular DA "show up"
> in such an analysis? The reason I ask is that when one reads about
> 6-OHDA being put into a discrete brain area, the authors present
> data showing that DA content in that area is reduced. I am
> interested in any comments or speculations, even if they are
> "outside of the mainstream." Rest assured that I am not a student
> trying to plagiarize your answers for a term paper, and any insights
> would be gratefully acknowledged in any published papers.
> Sincerely,
> Glen M. Sizemore, Ph.D.

Basically, you have it more or less right. It has been a while since I 
worked with 6-OHDA, but this is what i recall:

- the exact mechanism of toxicity isn't known, or at least it wasn't 
when I knew more about it. The speculation was that it disrupts the 
ability of mitochondria to deal with calcium (I mean, that is always the 
speculation for everything)

- 6ohda enters through the dopamine and norepinephrine reuptake 
transporters. It is toxic to DA and NE cells. You are correct that 
injections into the MFB will destroy the cells originating in VTA and 
SN. In my experience, there is diffuse brain damage as well, even with 
relatively small injections of 6-OHDA . However, this surgery is almost 
always done unilaterally (bilateral lesions produce a cessation of 
eating and drinking, although there are ways around that) and the other 
hemisphere is often used as a control.  The original papers for this are 
by Ungerstedt, although there are many many people since then using the 
technique. My old advisor at Michigan (Terry Robinson) uses the 
technique extensively.

- damage to NE sites is often (and usually) prevented by using the 
dopamine reuptake transport blocker desipramine at relatively high 
doses. This is how selective "DA" lesions are made (I think the paper is 
Breese & Traylor). There is also a DA reuptake inhibitor but it is 
difficult to get and has not been widely used to make selective NE 
lesions (for one reason, there is another selective NE toxin).  As for 
DA, MPTP is not effective in rodents, because it isn't converted to 
MPP+, but if you buy the latter you can use it in rodents. But it hasn't 
been used much in rodents, despite its recent popularity in monkeys.

- as far as how to measure DA, there are a lot of ways, you need to 
describe what is in the paper in more detail. But basically if you 
inject 6-OHDA any DA indicator will go down, except receptors which will 
go way up provided you kill enough of the input.

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