5-HT2A receptor agonist induced neurotoxicity.

[BilZ0r]

Why oh why are neurotoxicity researchers so mentally challanged? I read an abstract today, and I thought, "Fuck! someone has finally done a meaningul MDMA-induced neurotoxicity in cell culture paper".

I was wrong.

Still:

Neuroscience. 2006 Feb 25

Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia.

Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, Bastos ML, Meisel A, Carvalho F.

Rede de Quimica e Tecnologia, Toxicology Department, Faculty of Pharmacy, University of Porto, Porto, Portugal; Neurology Department, Charite Hospital, Humboldt University of Berlin, Berlin, Germany.

Studies on 3,4-methylenedioxymethamphetamine ("ecstasy")-induced neurotoxicity mainly focus on damage of serotonergic terminals.
Less attention has been given to neuronal cell death produced by 3,4-methylenedioxymethamphetamine and other amphetamines in
areas including the cortex, striatum and thalamus. In the present study we investigated 3,4-methylenedioxymethamphetamine-induced
neurotoxicity in neuronal serum free cultures from rat cortex. Since 3,4-methylenedioxymethamphetamine intake induces
hyperthermia in both animals and humans, the experiments were performed under normal (36.5 degrees C) and hyperthermic conditions
(40 degrees C). Our findings showed a dose-, time- and temperature-dependent apoptotic cell death induced by
3,4-methylenedioxymethamphetamine in cortical neurons. 3,4-Methylenedioxymethamphetamine-induced damage was potentiated
under hyperthermia. The neurotoxicity was reduced by the serotonin 2A-receptor antagonists, ketanserin and
(2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride, in both normothermic and hyperthermic
conditions. (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride, a model agonist for the serotonin 2A-receptor, also induced a
dose- and time-dependent apoptotic cell death. Again, protection was provided by ketanserin and
(2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride against
(+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced neurotoxicity, thereby indicating that the
3,4-methylenedioxymethamphetamine stimulation of the serotonin 2A-receptor leads to neurotoxicity. This study provides for the first
time evidence that direct 3,4-methylenedioxymethamphetamine serotonin 2A-receptor stimulation leads to neuronal cortical death.
alpha-Phenyl-N-tert-butyl nitrone a free radical scavenger and the nitric oxide synthase inhibitor Nomega-nitro-l-arginine as well as the
NMDA-receptor antagonist MK-801 provided protection under normothermia and hyperthermia, thereby suggesting the participation of
free radicals in 3,4-methylenedioxymethamphetamine-induced cell death. Since 3,4-methylenedioxymethamphetamine serotonin
2A-receptor agonistic properties lead to neuronal death, clinically available atypical antipsychotic drugs with serotonin 2A-antagonistic
properties could be a valuable therapeutic tool against 3,4-methylenedioxymethamphetamine-induced neurodegeneration.


Full Tex

So yeah, the finally heated the cultures up (which kills cultures a little bit anway), but the concentration of MDMA needed to induce neurotoxicity was still seemed pretty big (10-10uM probably the starting dose). Still, if 10uM is actually killing neurons, 100nM-1uM is probably pretty bad for them. Though again, the neurons were dying by themselves anyway. The question is of course: MDMA ISN'T NEUROTOXIC TO CORTICAL NEURONS YOU FUCKING PORTUGESE BASTARDS!!!. Why didn't they try and make mid-brain cultures containing serotoninergic neurons?

Importantly, DOI, the recreational, selective 5-HT2A receptor agonist was neurotoxic in a 5-HT2A receptor dependent manner, though the concentration needed was was into the uM range, and DOI probably only reaches a handful of nM in human usage.

Still, it's one to watch out for: you can no longer say "there is no evidence for hallucinogen induced neurotoxic".

 

[human]

The question is of course: MDMA ISN'T NEUROTOXIC TO CORTICAL NEURONS YOU FUCKING PORTUGESE BASTARDS!!!. Why didn't they try and make mid-brain cultures containing serotoninergic neurons?

I'm sorry, could you clarify and/or expand on this? Specifically, I'm being thrown off by "The question is of course: (not a question)." Also, I'm curious; why would or could mid-brain cultures containing serotonergic neurons provide for better conclusions than what they chose to use?

 

[fastandbulbous]

Cue the sound of BilZ0r banging head off wall screaming "you dozy fuckwits"!

Isn't it great when they don't specify, in terms of human use of such compounds that the neurotoxic dose is so much above the effective dose levels that neurotoxicity would be the least problem of a person taking a neurotoxic dose (like being catatonic & clinically insane from that sort of experience!). Bet you'll see it cited in govenment anti-drugs information though...

 

[BilZ0r]

I'm sorry, could you clarify and/or expand on this? Specifically, I'm being thrown off by "The question is of course: (not a question)." Also, I'm curious; why would or could mid-brain cultures containing serotonergic neurons provide for better conclusions than what they chose to use?

The question follows the statement that is not a question, you quote it: "Why didn't they try and make mid-brain cultures containing serotoninergic neurons?"

why would or could mid-brain cultures containing serotonergic neurons provide for better conclusions than what they chose to use?

As I say, MDMA isn't neurotoxic to cortical neurons, presumable because of the dearth of serotonin transporters, preventing MDMA (or a neurotoxic metabolite) entering the cells. MDMA is neurotoxic to serotoninergic neurons, one should test neurotoxicity against serotoninergic neurons.

 

[BristolRob]

I was under the impression that the serotonergic axons ascending into cortical regions were the most likely to be damaged by MDMA.

MDMA ISN'T NEUROTOXIC TO CORTICAL NEURONS

I'm not sure this is true. Animals have very little cortex anyway but I thought the most extreme regions are damaged and show the least recovery (Hatzidimitriou et al. 1999).

Via human imaging, it's hard to establish SERT loss in cortical regions because of the relative dearth of SERT, yes, but this is a methodological issue, and not evidence that human cortical cells are not damaged by MDMA use.

 

[BilZ0r]

I was under the impression that the serotonergic axons ascending into cortical regions were the most likely to be damaged by MDMA

Yes, but they still aren't cortical neurons are they, they're mid brain neurons with cortical prjections.

Animals have very little cortex? They have more than enough to do studies on, and it's constructed in the exact same way as human cortex is, on a cellular level.

The hatzidimitriou paper doesn't show damage to cortical neurons, again, it shows damage to the terminal fields of midbrain neurons.

Via human imaging, it's hard to establish SERT loss in cortical regions because of the relative dearth of SERT

What? Theres a lot of SERT in the cortex, it's one of the highest SERT expression areas.

 

[human]

Bah, it was late, should have taken everything following the colon as a whole.

Thanks for clearing that up though. I see what you're saying now.