The funding IS the science…

December 11, 2007

In a couple of comments to a recent post, people were exploring the concept of whether it matters if a particular individual is funded to do something since perhaps the other competing, well-funded labs will just do it anyway (start with this one). I would argue that this is wishful thinking. While there is some truth to the idea that only by accumulating a big pile of resources is one free enough to play around and take risks, established programs have a tendency to get conservative. So breaking up OldBoy type cronyism is a good goal.

As luck would have it, we have two RFAs (one doubles up for different mechanisms which is necessary with the new and idiotic grant packages) and a Program Announcement (with Set Aside Funding; “PAS”) from NIDA that let us pursue this a little more.

From the Guide:

YHN gave a little (p)review of the P20 in a prior post actually. NIDA seems to be putting on the full court press to launch new (full) Centers for the next decade. Are you paying attention DearDrugAbuseResearchReaders?

The first thing that jumps out to the casual observer is that these are hitting very hard on the clinical, translational and applied science buzz-concepts consistent with NIH-wide trends of late. When you delve into the PAS announcement you find a couple of interesting things, first of which is:

Effective pharmacotherapies have yet to be developed for cocaine, methamphetamine and marijuana addiction.

Yeah, no duh. We have not come up with much in the way of useful drug therapies for addiction. There are a few decent ones but for the most part these have come from agonist therapy concepts. Or from blind luck with approved meds being noticed as effective on the addiction as well as whatever else they were prescribed for. [Neuroscience luminary Floyd Bloom has occasionally given a fairly scathing run-down of all the lucked-upon drugs for mental disorders and I can tell you, the scientific enterprise is not looking good! Fortuitous findings followed by me-too-ism about sums it up. There’s a whole post about the virtues of fishing-expedition science versus hard hypothesis-driven in here somewhere…] The prototypical agonist therapy, by the by, would be methadone for heroin addiction or the nicotine patch/gum strategies for cigarette addiction. In neither case do these result from very high faluting theoretical science, I’d note. Then we get to the key:

Not of interest under this FOA are applications proposing the design and synthesis of DAT ligands

Suffice it to be said that NIDA’s drug discovery program has put a lot (and I mean a LOT) of eggs in the basket of dopamine transporter (DAT) ligands for stimulant (read, mostly cocaine) addiction. This is really just agonist therapy but the underlying body of research support focused on the DAT is un-freaking-believable so we can call this a clearly failed basic-science driven approach. In my view, it was a flawed area of endeavor from the start because it focused on the mechanisms of “feel-good”. The dopamine story in drug abuse is related to “reinforcing efficacy” of drugs which breaks down to how good you (or the animal subject) feel about acute drug exposure. This has very little to do with drug abuse and dependence. As I’ve touched on before, a whole ton more people get feel-good effects of drugs than become dependent.

And yet. How do you think those investigators who were bucking the trend faired over the past two-three decades of DA/acute reinforcement dominance of the NIDA pre-clinical research thinking? Poorly. And did those very well funded labs delve into different theoretical approaches or did they just keep chunking out the drugs-as-reinforcer self-administration pubs without thinking about translational or clinical relevance? One guess how NIDA feels about it, since you’ve read these Announcements.

As a little sidebar on grantsmanship the Program Announcements can be next to useless since they are broadly written and it takes some doing to come up with a relevant proposal that the I or C doesn’t already have something written about in an active PA. The PAS acts more like an RFA in the first year, making it of considerable more interest. For this one:

NIDA intends to commit a total of $1.5 million in FY 2008 to this Program Announcement with set-aside funds (PAS). Approximately 4-6 new awards will be made.

which you will recognize as standard RFA type talk.

Now moving on to the “Extinction” RFAs I have a mixed feelings. The central mandate is:

applications submitted under this FOA must: (1) propose to use an experimental paradigm that captures one or more of the processes associated with extinction and reinstatement or relapse of drug-seeking behavior, (2) propose to identify brain mechanisms or genetic differences involved in extinction, and (3) test justifiably relevant behavioral or cognitive (e.g., affective reappraisal, self-regulation) approaches and exogenous compounds or alterations of gene expression that may modulate or enhance extinction

On the one hand, good stuff because it is trying to model relapse to drug taking, not just feel-goodness of acute drug exposure. The “reinstatement” model of drug relapse is therefore a significant conceptual advance over straight reinforcer-efficacy self-administration models. In outline, the idea is that you train animals to self-administer drug to a stable level and then put them under extinction where lever pressing (or nose poking or what have you) is not reinforced with drug delivery. Over several (many) sessions, animals stop pressing the lever when put in the operant box. Then, one does something to the animal which produces an increase in lever pressing while the drug is still absent. The “something” can be stimuli (lights, tones, smells) previously associated with the availability of drug, stressors (mild foot shock) or, more usually, a small “priming” injection of drug administered before the session.

The flaw with this is that human-population drug abuse researchers and clinicians are often skeptical of reinstatement because the extinction process doesn’t really match with a human addict’s motivation to be abstinent. The latter is not just because they can’t find drug anymore but because they have “intent to quit” meaning other alternative sources of reinforcement and punishment of their behaviors. This component is essentially absent from animal models. So what I would have liked to see in this type of RFA would have been throwing it open to investigating new animal models of relapse, instead of betting the farm on a class of paradigms that are fairly well employed now anyway.

Given that now plenty of people are working on reinstatement models, WTF do we need an RFA for? Well, perhaps to put a big whuppin’ on internecine grant review warfare between the OldSkool reinforcement types and the reinstatement types? Are they crapping on each others’ grants? To de-emphasize the role of the human-populations researchers who don’t like extinction-reinstatement? Or just to convert their OldSkool types to TruBelieverz in reinstatement? I’m not sure.

And oh yeah, I’m sure as shootin’ thinking about whether I have a proposal for one of these, ya you betcha!

5 Responses to “The funding IS the science…”

  1. physioprof Says:

    “The flaw with this is that human-population drug abuse researchers and clinicians are often skeptical of reinstatement because the extinction process doesn’t really match with a human addict’s motivation to be abstinent. The latter is not just because they can’t find drug anymore but because they have ‘intent to quit’ meaning other alternative sources of reinforcement and punishment of their behaviors.”

    Do you really mean to imply that “intent to quit” is nothing more than a collection of “alternative sources of reinforcement and punishment of their behaviors”?


  2. drugmonkey Says:

    Well, I am a behaviorist at heart you know!


  3. physioprof Says:

    I hope you don’t have any children.


  4. […] I pointed out explicitly at least once ([Update: Original 2007 post]), research funding has a huge role in what science actually gets conducted. Huge. In my book this […]


  5. clifford e green III Says:

    I believe that focus upon endogenous morphine production in the ventral tegmental region of the LMS will probably pan out to be an important area of the brain to study/form a strategic plan to augment addiction therapies……but not without a paradigm shift in human culture led by science but not FORCED by scientific investments.

    recent studies suggest that endogenous morphine production in the brain is increased when habituation/tolerance to nicotine, methamphetamine, ethanol are established in the animal model.

    my thought is that the disparate neurotransmitter types represented in that hypothesis might suggest that behavioral reinforcement of habituation and physical dependence could involve increases in endogenous morphine production with a large number of neurotransmitters, and include as well endogenous neurotransmitters that are released by activities such as exercise, sex, risk taking, and hedonic/pathological acts etc. Endogenous morphine I expect will follow along with the peptide opioids that for decades are thought to be important players in neurogenesis/neuroplasticity development of the fetus and the brain that develops past birth, consider beta endorphin and its close allied activities to that of morphine in regards to mu opioid agonism.

    what will be an obvious need in the future is the acceptance of an expanded perimeter of habituation and addiction tolerated by society that extends beyond the currently imposed. Religious, socio economic, and the ever present industrial yoked expectations are self limiting and also based upon a sort of choke chain reaction. Only when proper funding exceeds the glut of corruption based economy.

    I sometimes wonder if the researchers involved with the morphine conjugate vaccines and other drug utilizing conjugate vaccines have taken into account the occurrence of endogenous morphine production in the brain, and especially the gene encoded production of morphine via white blood cells in response to sepsis infection. ( if any researchers involved with this technology have indeed considered the E. M. issue I would love to hear about that subject )

    I myself sought treatment of most known approved heroin addiction therapies that existed up until around 2005. At that point I took my own direction involved with various phytochemical agonists/antagonists of the various opioid receptor types found in various plants…..a growing list of proven opioid agonists/antagonists exist in nature, and other receptor type agonists/antagonists that are now being thought to be involved in dependency issues. The list of compounds found in plants and animals that might have purported benefit for opioid research, is 10x that at least of the proven field…..and given the disparate types of structures that are involved, I will assume there will be too many for an economic crisis yoked and ecosystem collapsed society to do much with besides follow along with societies unapproved implementations. A supply and demand ecological nightmare that has already blunted the force of brilliance.


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