"Mephedrone Does not Cause Neurotoxicity to Dopamine Nerve Endings of the Striatum"

[holdout]

"Mephedrone Does not Cause Neurotoxicity to Dopamine Nerve Endings of the Striatum"



Journal of Neurochemistry (Dec. 2011) http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2011.07632.x/abstract
Mephedrone, an Abused Psychoactive Component of “Bath Salts” and Methamphetamine Congener, Does not Cause Neurotoxicity to Dopamine Nerve Endings of the Striatum
Mariana Angoa-Pérez1,2, Michael J. Kane1,2, Dina M. Francescutti1,2, Katherine E. Sykes1,2, Mrudang M. Shah2,3, Abiy M. Mohammed2,3, David M. Thomas2,4, Donald M. Kuhn1,2

Abstract
Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the US and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4X 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum.

[edit: I need to learn to speak with an 'inside voice']so i dont wanna hear about a mother crying about her son who died after consuming PMMA in an "E" tablet. if the world hadn't banned safer substances such as 4-methylmethcathinone, many lives of teens would be spared to this day. the war on drugs is self-inflicting and teens are paying the price with their lives because of ignorant adults who think all organic compounds should be banned/scheduled. ultimately they will seek to ban things like sucrose and sodium chloride lmao -- yes -- drug war activists are that ignorant! labeling something as "BAD" is not the same as understanding the science behind what you're trying to govern in the lives of people around you. just like politicians make laws about things they know nothing about.

 

[kaskelot]

All right. So it doesn't cause Parkinsons at first binge.

That we knew.

How about serotonergic cardiotoxicity? Serotonergic neurotoxicity? Hepatotoxicity?

Hell, how about bad behavioural influence? It's making most people prance around it in a trot like a show horse (from first binge), worshipping even its horrible smell.

 

[ebola?]

All right. So it doesn't cause Parkinsons at first binge.

That we knew.

No, "it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels."

Treatment with high-dose methampetamine or even MDMA will cause such changes, ostensibly denoting potential for neurotoxicity. That high dose, repeated administration of mephedrone does not cause this (work out 20 to 40 mg/kg for a human...it's a hell of a lot ) is rather surprising.

ebola

 

[kaskelot]

No, "it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels."

Treatment with high-dose methampetamine or even MDMA will cause such changes, ostensibly denoting potential for neurotoxicity. That high dose, repeated administration of mephedrone does not cause this (work out 20 to 40 mg/kg for a human...it's a hell of a lot ) is rather surprising.

ebola

True. I got caught up in the tone of the original post. To me these results sure seems a bit promising and a bit surprising (I expected some of the methcathinone/methamphetamine effects to be there), but the conclusions OP made seems quite far fetched.

 

[nAON]

Serotonin effects are mentioned briefly in the article, may be worth looking up the thing they're referring to;

Surprisingly little is known about the neurotoxic potential of MEPH beyond the recent observation that repeated treatment of rats
causes persistent serotonergic deficits (Hadlock et al. 2011)

 

[Epsilon Alpha]

Shire are you reading this? Research sustained release substituted amphetamines!
But yeah, its very interesting indeed. Gotta wonder what mechanism this is through and how it reflects the mechanism of amphetamine induced toxicity.

However...

While our manuscript was in preparation, it was reported that MEPH causes long-term deficiencies in 5-HT neurochemical function of rats (Hadlock et al. 2011)

Study is below:
http://jpet.aspetjournals.org/content/339/2/530.short

The designer stimulant 4-methylmethcathinone (mephedrone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone. Mephedrone has been readily available for legal purchase both online and in some stores and has been promoted by aggressive Web-based marketing. Its abuse in many countries, including the United States, is a serious public health concern. Owing largely to its recent emergence, there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone. Accordingly, the purpose of this study was to evaluate effects of this agent in a rat model. Results revealed that, similar to methylenedioxymethamphetamine, methamphetamine, and methcathinone, repeated mephedrone injections (4× 10 or 25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to mimic psychostimulant “binge” treatment) cause a rapid decrease in striatal dopamine (DA) and hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter function. Mephedrone also inhibited both synaptosomal DA and 5HT uptake. Like methylenedioxymethamphetamine, but unlike methamphetamine or methcathinone, repeated mephedrone administrations also caused persistent serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release from a striatal suspension approaching that of methamphetamine and was self-administered by rodents. A method was developed to assess mephedrone concentrations in rat brain and plasma, and mephedrone levels were determined 1 h after a binge treatment. These data demonstrate that mephedrone has a unique pharmacological profile with both abuse liability and neurotoxic potential.

My main interest is the lack of microglial activation, which would suggest some sort of anti-inflammitory action in the brain or a lack of a metabolite that is capable of activating them. That's one reason ASA is something I push hard in my amphetamine thread.