Donor's Choose Time!!!

October 22, 2012

Yes, folks, it is that time of year. You get to open up your wallets, even $5 helps people, to help little kids’ school classrooms. It is no secret that public education has been enduring a long downward slide in the ranks of things that are important to voters/taxpayers in the US. But you probably didn’t know just how bad it has gotten. Peruse these projects, see the things that you remember as having been the expected value (like dissection in 10th grade Biology) and wonder that this is no longer the case.

Then give. The kids will benefit.

The sole purpose of generating a review article that lays out your GrandeTheoryeEleven in the biomedical sciences is so that you can try to take sole credit for ideas that occur to many members of your subfield who are following the same literature that you do.

Please note that Nobel Prizes in Physiology or Medicine are not generally handed out for review articles.

siiigh.

that is really what I find so distasteful of this whole affair. The witch-hunt being carried out by some of these commentators reeks of McCarthyism like persecution to seek out “impure thoughts” and destroy those who may harbor them. There is ZERO EVIDENCE that DM is actually sexist, other than an idiotic comment he placed on facebook.

There is no better way to address this than with illdoctrine

Repost: I Am…

October 19, 2012

There was a blogpost responding to the Maestripieri comment that noted a tendency for more mainstream outlets to emphasize the complaints of women over those of men. I rush to disagree since it happens that Isis and Janet Stemwedel are eloquent and quote worthy. My post was little more than a “don’t do this”.

Nevertheless it would be bad if there were any impression generated that only women thought the remarks of Maestripieri were out of line. Men object too.

Although this is only part of a complex reason, I was reminded of this previous observation of mine.


I am a friend. A friend to women who I met when I was 5 years old, ones I met in high school, college, grad school. Women I met as a postdoc, as a faculty member, as an inhabitant of my community. They work in any number of professions from publication to politics to public health to scientific research to mainstream media to education, etc, etc. Many different walks of life. Many of them experience uncomfortable moments, sustained toxic work environments and/or flagrant discrimination in their working lives. I like my friends. Their continued happiness and well being is important to me.

Read the rest of this entry »

There are two new pharmacological investigations on the substituted cathinone drugs that have been discussed here on occasion.

Each of

Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW.Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products. Neuropsychopharmacology. 2012 Oct 17. doi: 10.1038/npp.2012.204.

and

Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME.Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2012 Aug 17. doi: 10.1111/j.1476-5381.2012.02145.x.

report very similar findings for MDPV, the cathinone that appears most frequently in US newspaper reports.

As a very general rule, the amphetamine class stimulants do a couple of things to enhance the neuron-to-neuron chemical communication that occurs in the brain. The most common and significant effects tend to involve the transporter mechanisms that remove dopamine, norepinephrine and / or serotonin from the synapse, the gap between two neurons. These transporter molecules are an integral part of terminating a signalling event which has been caused by the release of one of these three monoamines from one of the neurons in question. Interfere with the operation of these transporters and a drug can potentiate the magnitude or duration of a given signalling event (i.e., release of one of the dopamine (DA), norepinephrine (NE) or serotonin neurotransmitters).

The amphetamine class stimulants have these properties. As does cocaine. As do therapeutic drugs such as methylphenidate (Ritalin) and Prozac. The term selective serotonin re-uptake inhibitor, SSRI, for Prozac-class antidepressant drugs refers to the transporter, obviously, and also indicates a key thing with the term “selective”. Drugs which have the ability to interact with one of the monoamine transporters tend to interact with the other ones as well. Substantial differences in effect can be associated with differences in the relative ability a specific molecule has to attach to the DAT versus the NET versus the SERotonin transporter (SERT). As one clear example, methamphetamine and MDMA differ in their relative ability to inhibit the SERT….this property of MDMA is associated with many of it’s stimulant-atypical properties relative to other amphetamine-class drugs.

The new studies both show that MDPV blocks all three transporters with much more potent effects at the DAT and NET relative to SERT. As Baumann and colleagues note, MDPV is 50 and 10 times more potent than cocaine (not an amphetamine, we’ll come to this) at DAT and NET respectively. Simmler and colleagues similarly indicate that MDPV is much more potent at DAT than cocaine or methamphetamine which did not qualitatively differ from each other.

So to this point, MDPV looks like a high-potency traditional stimulant. Most effective at the DAT, fairly effective at the NET and with less ability to block the SERT.

Cocaine and the amphetamines diverge at this point because the amphetamines act as a substrate at the transporters. Instead of only interfering and blocking them from doing anything, the amphetamines actually substitute for the neurotransmitter in question and are taken up into the cell. In so doing, they also cause an exchange to happen whereby the transporter moves some neurotransmitter from inside the cell back into the synapse. This transporter mediated efflux contributes to any “regular” release of neurotransmitter mediated through the merging of intracellular sacs (called vesicles) with the cell membrane.

The two papers agree in finding that MDPV has no ability to cause transporter-mediated efflux of dopamine and is therefore best categorized neuropharmacologically as a “pure” blocker (like cocaine) rather than an amphetamine-like transporter substrate.

The Simmler paper adds an in vitro model of blood/brain barrier penetration…in very simple terms the degree to which a molecule is fat-liking versus water-liking can alter the speed at which it can cross cell membranes and get into the brain. This paper used an in vitro preparation of human capillary endothelial cells (that form the blood-brain barrier) to show that MDPV is likely to cross the blood-brain barrier very rapidly, consistent with high lipophilicity predicted from its structure.

The upshot of the two papers is that MDPV shows pharmacological properties consistent with classical stimulants. It shows relatively high selectivity for DAT over SERT and high potency relative to drugs such as methamphetamine or cocaine. In vivo neurochemistry in the Baumann paper confirm that MDPV has potent effects on dopamine levels in the nucleus accumbens, a hallmark of drugs (beyond the stimulants even) which have substantial risk for compulsive use. The only somewhat discordant note for the structure-activity nerds is that MDPV looks so much like the rest of the amphetamines and cathinones that it will be interesting to discover why it doesn’t act as a transporter substrate (Simmler et al included a number of other cathinones and showed that many of them do act as transporter substrates.)

Together these papers suggest that MDPV has high abuse liability with a use pattern characterized by frequent re-dosing much like one sees with cocaine. This is consistent with many self-reports that are emerging from people who use MDPV and therefore, despite the relatively brief time on the “market”, we can predict a cocaine-like dependence problem to emerge for MDPV in the near future.

It’s quite possible that the full-throated value of a scientific meeting for your science is only realized once you are a PI.

It is not infrequent that I come back from scientific meetings all in a tizzy to do one of three things.

1) Put the hurry up on pumping out some data that we’ve been collecting.

2) Start new experiments! Several. We gotta get on this right now people so let’s moooooove!

3) Write two or three new grant proposals.

The reasons are varied but it all comes down to the constellation of encouragements you get at a conference through talking with various people about your data and their own data.

This is why we do this. Because the science is exciting. And meetings put a thick underline below this experience.

I don’t actually know Dario Maestripieri although I have read some of his scientific work now and again over the years. His areas of interest include primate social behavior as well as mating systems and reproductive strategies. Apparently his interest extends to the human primate.

Professor Maestripieri has posted a rather idiotic observation about the Society for Neuroscience meeting and his apparent disappointment in the lack oI eye-candy available for his personal enjoyment. Now yes, he posted this on Facebook which is nominally private-ish. But clearly he has enough “friends” that someone was offended and saw fit to screen capture and send it around.

There is a very simple response here. Don’t do this. It’s sexist, juvenile, offensive and stupid. For a senior scientist it is yet another contribution to the othering of women in science. In his lab, in his subfield, in his University and in his academic societies. We should not tolerate this crap.

Professor Maestripieri needs to apologize for this in a very public way and take responsibility for his actions. You know, not with a nonpology of “I’m sorry you were offended” but with an “I shouldn’t have done that” type of response.

UPDATE: I have now heard this tale from about a half dozen independent directions. Several people expressed thanks to me and mentioned their channel on the info hesitated to publicize for fear of some sort of retaliation. Well, the cat is well and truly out of the bag and there are multiple lines of revelation on this. If you are one of the original sources, you have company. I thank you all for bringing this behavior to light.

As always, feel free to sock up in the comments, use something other than your usual in the email field though.

See Janet’s post here.

And Isis’ post.

And Jezebel.