ALCAR, meth, bupe, and DA depletion

[:^)]

http://www.ncbi.nlm.nih.gov/pubmed/12853314

Some of the damage to the CNS that is observed following amphetamine and methamphetamine (METH) administration is known to be linked to increased formation of free radicals. This increase could be, in part, related to mitochondrial dysfunction and/or cause damage to the mitochondria, thereby leading to a failure of cellular energy metabolism and an increase in secondary excitotoxicity. The actual neuronal damage that occurs with METH-induced toxicity seems to affect dopaminergic cells in particular. METH-induced toxicity is related to an increase in the generation of both reactive oxygen (hydroxyl, superoxide, peroxide) and nitrogen (nitric oxide) species. Peroxynitrite (ONOO(-)), which is a reaction product of either superoxide or nitric oxide, is the most damaging radical. It can be reduced by antioxidants such as selenium, melatonin, and the selective nNOS inhibitor, 7-nitroindazole. METH-induced toxicity has been previously shown to increase production of the peroxynitrite stress marker, 3-nitrotyrosine (3-NT), in vitro, in cultured PC12 cells, and also in vivo, in the striatum of adult male mice. Pre- and post-treatment of mice with l-carnitine (LC) significantly attenuated the production of 3-NT in the striatum after METH exposure. LC is a mitochondriotropic compound in that it carries long-chain fatty acyl groups into mitochondria for beta-oxidation. It was shown also to play a protective role against various mitochondrial toxins, such as 3-nitropropionic acid. The protective effects of LC against METH-induced toxicity could be related to its prevention of possible metabolic compromise produced by METH and the resulting energy deficits. In particular, LC may be maintaining the mitochondrial permeability transition (MPT) and modulating the activation of the mitochondrial permeability transition pores (mPTP), especially the cyclosporin-dependent mPTP. The possible neuroprotective mechanism of LC against METH-toxicity and the role of the mitochondrial respiratory chain and the generation of free radicals and their subsequent action on the MPT and mPTP are also being examined using an in vitro model of NGF-differentiated pheochromocytoma cells (PC12). In preliminary experiments, the pretreatment of PC12 cells with LC (5 mM), added 10 min before METH (500 micro M), indicated that LC enhances METH-induced DA depletion. The role of LC in attenuating METH-evoked toxicity is still under investigation and promises to reveal information regarding the underlying mechanisms and role of mitochondria in the triggering of cell death.

A few things:

1. Does this necessarily mean co-administration of meth and L-Carnitine results in increased dopamine depletion? I'm assuming that's what they mean by "enhances".

2. If so, would it be reasonable to assume the same applies to amphetamine in place of meth?

3. In this light, what are your thoughts on co-administering bupropion (a DARI and NERI) with L-Carnitine? I realize this would probably be guesswork without more information but I'd love to hear ideas.

 

[Solipsis]

I *think* that enhances means something like indirectly attenuating, I've seen the term used more often and it seems to point to a mechanism action more efficiently and showing less toxicity or cost of work, but still with similar end results.

2. Well be careful about assuming but we might hope to see similar results there, from what I understand of it.

http://www.ncbi.nlm.nih.gov/pubmed/12486488

The present study aimed to investigate the protective effects of melatonin, ethanol and temperature changes on methamphetamine-induced neurotoxicity in both sexes of mice. Mice exhibited a similar degree of striatal dopamine depletion when methamphetamine was administered during the light and dark cycles. Moreover, 10 mg/kg, but not 5 mg/kg, of methamphetamine, significantly increased body temperature even though dopamine depletions were observed following both doses. Melatonin (80 mg/kg) dissolved in 30% (v/v) ethanol and 30% ethanol alone exerted a moderate to full protection against methamphetamine-induced dopamine depletions in both sexes of mice, whereas the same dose of melatonin in 3% ethanol exerted no protective effect. Furthermore, ethanol attenuated methamphetamine-induced dopamine depletions in a dose-dependent manner with the exception of high efficacy of ethanol at low doses. Finally, the protective effects of ethanol were not blocked by bicuculline. Together, we conclude that ethanol may protect mice against methamphetamine-induced dopamine depletion probably via non-GABAA receptor activation.

Of course mice are not humans, and assuming anything would mean that it is good to drink some alcohol plus melatonin with meth... although it might have to be injected in concentrated ethanol solutions...

3. No I don't think bupropion can really be compared it does other things to the brain. The dopaminergic effects can help with confidence and motivation when using bupropion, but the increased levels of DA/NE also tend to produce insomnia and restlessness. I don't think depletion is really a concern, let alone one that could be helped with ALCAR.

 

[Seppi]

In excessive doses, both drugs induce ROS generation through dopamine autoxidation and MAO-metabolism of dopamine in humans. That form of toxicity is primarily a consequence of an excessive release of dopamine than an excessive amount of the drug itself. Meth has more mechanisms (mostly oxidative) to induce damage than amph due to how it interacts with the BBB and presynaptic structures though; amphetamine (not meth) toxicity seems to be mediated solely via dopamine.

What that boils down to is:
No dopamine release + lots of amphetamine = no toxicity
No dopamine release + lots of methamphetamine = still some toxicity
Lastly, it means that antioxidants can mitigate toxicity from amphetamine abuse, but won't be as effective in methamphetamine abuse.

Read this thread if you want more of an explanation... it's sort of long though. The mechanisms of meth toxicity in humans are somewhat technical.

Edit: More relevant to the questions in this thread, both are inhibitors of the high affinity carnitine transporter

 

[:^)]

Thanks to you both for the replies, interesting info. Can anyone chime in particularly on Solipsis's ideas for the meaning of "enhances" in this context? It would be unfortunate, for instance, if one were to co-administer (A)LCAR and (meth)amphetamine with one intent being to reduce DA depletion only to find that "enhances" was meant to convey the idea of 'increases'.

 

[:^)]

Anyone? I haven't been able to find any reason to strongly believe it has one meaning over the other opposite meaning. I'm hoping for Solipsis to be right, meaning co-administration would be a safety measure rather than a dopamine death sentence. Perhaps someone with a paper using the word in which its meaning is obvious, or any other insight?

 

[ParappaTheRapper]

Not sure about dopamine, but i know caritine requires fat, like fatty acids to enter the mitochondria,

 

[m060mm]

I've also heard contrary evidence about NAC resulting in pro-oxidative states and DA depletion (or was it DA receptor downregulation?)