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Potentiating amphetamine by inhibiting dopamine breakdown

seep

Bluelighter
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Nov 28, 2008
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Does anyone know of anyone potentiating amphetamine by inhibiting dopamine beta hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine? Clinical results are a mixed bag and usually are presented from the point of view of addiction . But they are interesting:

Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts DA to NE (Karamanakos et al., 2001; Vaccari et al., 1996). As a result, synaptic NE levels decrease relative to DA . . .

Disulfiram’s efficacy for amphetamine addiction has not been examined until recently. Disulfiram enhanced both amphetamine induced pleasurable (“high” and “drug liking”) as well as unpleasant (“anxious” and “bad drug effects”) subjective effects, but did not affect d-amphetamine-induced increases in heart rate or blood pressure (Sofuoglu et al., 2008b). Disulfiram, through inhibition of the enzyme dopamine β-hydroxylase, may increase the amount of dopamine in the brain by blocking dopamine’s conversion to norepinephrine and thereby increasing the amount of dopamine that amphetamine can release (Karamanakos et al., 2001). The active release of dopamine from noradrenergic neurons terminating on the nucleus accumbens would likely increase amphetamine’s positive and negative subjective effects, as observed. From a treatment perspective, although disulfiram might reduce amphetamine abuse by amplifying amphetamine-induced anxiety and “bad drug effects”, making the experience aversive in the same way it does the experience of alcohol intoxication, it might also increase abuse potential by enhancing “high” and “craving”. How these disulfiram-induced increases in both positive and negative subjective responses to amphetamine affect actual drug use remains to be determined empirically in future studies.

source

mixed bag, but the article's written from the point of view of addiction medicine

which is why experience reports would be kind of nice if anyone knows of someone whose combined amp with an effective DBH inhibitor.

thanks
 
Since you neglected to, let me point out the obvious - disulfiram is not going to be a tolerable dopammine beta-hydroxylase inhibitor for most people that would have an interest in this because it is also a potent inhibitor of acetaldehyde dehydrogenase. It is thus marketed for use in alcohol dependence (trade name Antabuse) Thus, if anyone is going to experiment with this compound, avoid ethyl alcohol like the plague!
 
I dont understand

"The subjective effects of amphetamines in humans
seem to be correlated with their capacity to release NE rather than DA"

"inhibition of enzyme dopamine B hydroxylase causes less NE MORE DA "

shouldnt the subjective effects be caused by DA rather than NE like the first quote said

or does the less NE directly cause more DA?

because if that's what the author means he has a strange way of phrasing it

because the gist i got of it is the excess DA is what causes the increase in subjective effects not the less NE
 
Disulfiram, through inhibition of the enzyme dopamine β-hydroxylase, may increase the amount of dopamine in the brain by blocking dopamine’s conversion to norepinephrine and thereby increasing the amount of dopamine that amphetamine can release

so its not stopping NE that causes more DA .its stopping DA from turning into NE that causes more DA

so why does the article say:

"The subjective effects of amphetamines in humans
seem to be correlated with their capacity to release NE rather than DA"
so why does the article say
 
I could be completely wrong, but I imagine that the physical effects associated with amphetamine use may be correlated with NE levels. Atomoxetine feels physically similar to amphetamine (well, excepting the vomiting) but mentally it's not the same at all. The physical feelings within the body are important for subjective effects.
 
The paper I link to (a very readable one), goes into detail about all that. Interestingly about atomoxetine,

Recently, our laboratory examined atomoxetine’s effects on the acute physiological and
subjective responses to d-amphetamine in healthy volunteers (Sofuoglu et al., 2008a). Four
days of atomoxetine treatment attenuated the increases in systolic and diastolic blood pressure,
and cortisol induced by 20 mg/70 kg d-amphetamine compared to placebo. Atomoxetine also
attenuated some of the subjective effects, including ratings of “stimulated”, “good drug
effects”, and “high”. Our findings are consistent with preclinical studies that suggest that NE
contributes to acute amphetamine responses, including its subjective effects. The contrast
between atomoxetine’s effects on cocaine compared its effects on the amphetamine high could
be due to the greater contribution of the NE system to the production of amphetamine’s effects,
compared with cocaine.

How does atomoxetine attenuate the subjective, physiological, and endocrine effects of damphetamine?
As many preclinical and clinical studies indicate, NET inhibitors acutely
increase NE activity. However, whereas tonic NE activity stays elevated with prolonged
treatment, the noradrenergic response to pharmacological and behavioral challenges is
attenuated, possibly due to increased stimulation of inhibitory α2-adrenergic autoreceptors as
well as down-regulation of the post-synaptic noradrenergic receptors by tonic NE elevation
(Szabo and Blier, 2001).

I'm aware that norepinephrine plays a role in the therapeutic value of amphetamine. But I'm concerned here with the intensity of the high.

ziddy, good point. I mentioned disulfiram cuz it's relatively easy to get and there aren't many DBH inhibitors out there. Perhaps when nepicastat becomes more widely available...
 
Wouldn't that be pretty much like taking a MAO-B inibitor or some L-dopa (or even a DRI).

Any way with a little bit of research I came across quite a few DBH inhibitors.

Fusaric acid
Tropolone
Nepicastat
Benzyl and pyridyl thioimidazoles (aka mercaptoimidazoles)
As I expected some beta substitutions would block DBH, this one irreversably (I wonder about betamethylPEA).
Betacyanophenyethylamine

DBH inhibitors might also counteract the metabolism of various amphetamine like stimulants since beta hydroxylation is one of the common steps for PEA metabolism (eg: Amphetamine --> IPA).

Still I keep my worries about the hypotension side effects.
Some research on phenylalanine-hydroxylase, tyrosine-hydroxylase and phenylethanolamine-N-methtranferase inhibitors could be interesting.
Isn't it funny that methamphetamine gets N-demethylated to later be N-methylated if not broken down first by MAO?
 
Also DBH needs a copper ion and other cofactors like ascorbate and fumarate ions to exert it's function. Disulfiram blocks DBH by copper chelaton just like diethyl-dithiocarbamate. There are quite some concerns regarding copper chelation/depletion in the organism since it is involved in a number of important biological functions:

Wiki:
"Copper is incorporated into a variety of proteins and metalloenzymes which perform essential metabolic functions; the micronutrient is necessary for the proper growth, development, and maintenance of bone, connective tissue, brain, heart, and many other body organs. Copper is involved in the formation of red blood cells, the absorption and utilization of iron, the metabolism of cholesterol and glucose, and the synthesis and release of life-sustaining proteins and enzymes. These enzymes in turn produce cellular energy and regulate nerve transmission, blood clotting, and oxygen transport."

Some of the info came from this book:
"Il feocromocitoma ed il sistema adrenergico"
(I know it's in Italian but seep speaks fluent Spanish it seems, so he won't have much of a struggle reading it.)

Another very short article I found (still Italian) discusses an experiment ought to determine neurotoxicity changes in rats administered with methamphetamine or MTPT along with fusaric acid over a 9 week period.
The conclusion was nothing good, seems that DBHI administration along with amphetamine like stimulants extends the neurotoxicity caused by dopamine levels and causes slower neuroregeneration of noradrenergic neurons.

"L'inibizione transitoria dell'enzima dopamina beta-idrossilasi estende ai neuroni noradrenergici i processi di neurodegenerazione."
 
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lol you overestimate my ability to read Italian. I can barely read Portuguese.

Disulfiram blocks DBH by copper chelaton[/I][/URL]

oh that's what it does. Good to know it's not irreversible, which was my primary concern.

Fusaric acid sounds like a chemotherapy agent. Same with tropolone? Scary side effects there.

There are naturally-occuring MAOIs in many foods and OTC supplements. I wonder if there are natural DBHIs within reach.

ps: are there any metallic elements your country isn't obsessed with?
 
I always had this wierd feeling, that maybe Disulfiram inhibits Tyrosine Hydroxylase, along with Dopamine Beta-Hydroxylase. It just seems that it would make sense.


Norepinephrine release Definitely has to be more important than it looks at face value, in terms of the dopamine-increasing effects of Amphetamine. Besides the alpha-1 adrenergic receptor, there is beta-3. Antagonizing both of those, blocks MDMA-induced hyperthermia. Beta-adrenergic activation induces tyrosine hydroxylase activity, [but ,....is that because of just beta-3 activation, or are beta 1/2 important]
 
dopamine breakdown wouldn't affect vesicular norepinephrine release. Think about it.
 
dopamine breakdown wouldn't affect vesicular norepinephrine release

"Breakdown" initiated and mediated by which enzymatic pathway? Given your OP, you seem to have been of quite an opposite persuasion yesterday. When sufficiently catabolized by DA-beta-hydroxylase in colocalized catecholaminergic neurons, 'dopamine breakdown' most definitely does influence the subsequent concentration of noradrenaline released from the cystosol into the extracellular compartment, albeit weakly in humans.

On the other hand, about as much dopamine is neutralized via oxidative metabolism by MAO and O-methyl transfer reactions. Neither of those means of catabolism would have any direct adrenergic influence in the context of dopamine degradation.

Norepinephrine release Definitely has to be more important than it looks at face value, in terms of the dopamine-increasing effects of Amphetamine.

And that's what fucks me and just about every other meth-head I know. It seems that many of the peripheral 'adrenergic' side effects are more-or-less inextricably linked to the mechanisms by which amphetamines' subjective effects are fully realized, at least in humans. This wretched fact compels me to sit content with my alpha blockers and hope that psychostimulants with increasingly greater BBB permeability and central specificity are developed in the near future [as opposed to more redundant analogous/reformulated variants of +100 year-old alpha-methylphenethylamine].
 
maybe I missed a plot point, but norepinephrine production and norepinephrine release seem like 2 discrete processes

I'll have to look more deeply into how the 2 processes intergoo w/r/t the amphetamine experience
 
but norepinephrine production and norepinephrine release seem like 2 discrete processes

They are. But one could easily reach the conclusion that the bulk of available intracellular noradrenaline will ultimately find itself packed within the synaptic vesicles at the terminal button, and thus will directly correlate to the eventual quantity released.

Now as far as the actual process is concerned, extracellular noradrenaline concentrations (which are, of course, dependent upon the previous intracellular concentration prior to action potential) are in fact often inversely correlated to intracellular concentrations following release, given the stifling influence of the alpha-2A adrenergic autoreceptors upon intracellular catecholamine synthesis via tyrosine hydroxylase. On the other hand, depending upon the particular region of interest (as different neurons express differing quantities of membrane-bound proteins), the sweeping action of the transporters could easily compensate for the inhibitory effect of the autoreceptors, in which case the correlation is neutral.

Within the context of amphetamines, on the other hand, synaptic release is non-vesicular, and therefore not subject to the restrictive gate control of electric potential difference. This 'voltage independence,' coupled with the fact that the transporter is spitting out amines in reverse, leaves little room for concern regarding the typical inhibitory confounds. Any NE taken up and/or synthesized by the neuron will be promptly dumped out of the cell by the abhorrently functioning uptake pump as long as the releasing agent remains enzymatically unmolested within the terminal.

I see now what you were trying to say, but your observation doesn't change the end result. As long more neurotransmitters are available for release within the vesicles (all other things being equal), there will be a net increase in synaptic NE transmission, whether amphetamine is present or not (but especially with amphetamine present).
 
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