Hey Cumol ,
For my university (the college of wooster) we were required to start an original research project, design it with help from a faculty advisor, then carry it out, and write it up. I had an interest in ketamine after reading a few articles suggesting that it had some antidepressant effects in small human studies. It is especially interesting for at least 3 reasons to my mind: 1. It has a very rapid onset, unlike traditional anti-depressants 2. In humans, it seems to have some serious longevity (1 dose, in a few studies, has led to people feeling significantly different for as long as a few weeks, some for over a month) 3. It seems (in humans) to be effective in patients who are resistant to traditional antidepressants. Now, there is one big negative that leaps out at me; it is a drug of abuse, so there is potential in an at risk population (ie. those who are depressed) for some serious complications, if they were asked to self administer. Now, we have quite a few small studies in humans, documenting that ketamine seems effective, and seems rather persistent after just a small dose. But in the papers I read through, it seems that you would be hard pressed to find anything so consistent in rodent models. Most studies in rodents dealt with serial doses, and those that dealt with acute doses had some very mixed results. I could dig out the paper if you are interested in this background. My study was trying to see if previous studies had failed because of using different models of depression in the rodents, or if using different models would produce similar effects as we observe in human models. This is important because, as you probably know, animal models allow many times more subjects, and ones we care less about, than does human testing. If we could find a model which nicely correlates depression and ketamine treatment in rodents with the results already seen in humans, we could do quite a bit more preliminary testing, and boulster the idea of using it in humans. Admittedly, this is not the most exciting project. Or, at least, not to the people I've talked to about it. Anyway. The study went something like this:
I used Wishart Rats (around 35 of them)
I had 3 "Model of Depression" groups: Control, Chronic Moderate Stress, and Learned Helplessness.
I had two Drug Conditions: Saline (control), and Ketamine.
I evaluated the depressive symptoms via the Forced Swim Test. Basically, you're putting the subject in a tub of water they cannot escape from, and you compare active behaviors like swimming and climbing vs. inactive behaviors (floating), then use the relative amount of each behavior to judge "depression behaviors". I am not sure who came up with this, but it is fairly well regarded now, since SSRI's/other established anti-depressants tend to increase active and decrease passive behaviors when administered. And I examined the effectiveness of the models at inducing depressive symptoms, and ketamine at treating the depressive symptoms. Basically, there were no results to speak of. When we compared rats in the behavioral control condition to the other two groups (LH and CMS), we did not observe a significant difference. Which was disappointing to me, but that's how research goes sometimes, I suppose. Anyway, I would have been curious to see some molecular measures of my study or a similar study (measuring BDNF perhaps?). I am curious to hear if you have any feedback on the study. Molecular medicine sounds like a tough-as-nails proposition. Is that the field you currently work in?
I actually find the study important. You have a question to answer and you find the best way to answer it. It also has clinical relevancy and establishing or reevaluating animal models is important work. You shouldn't have the feeling that you didn't do much. You did more than many medical doctorates that I know of :D I finished my masters in molecular medicine in april 2014. Its life sciences with a strong focus on biomedical research. Pretty interesting and fun :) I just started my PhD at an axon regenration lab. We investigate the molecular mechanisms of axonal regeneration by using the optic nerve as our model. While the work is interesting, I will not continue my PhD here. I have always been interested in psychedelic research and the molecular basis of psychedelics and other psychoactive substances. Therefore I am trying to read my way through literature and maybe find a lab here in europe that would fulfill my curiosity towards this area of research :) What are your plans? Whats coming next?
Thanks! Axon regeneration sounds interesting, I only know a small bit about that; if I'm remembering correctly, axons regenerate more easily in the PNS compared to the CNS. In the CNS scar tissue generally hinders the regeneration? And this is somewhat due to the neurons themselves, but also has to do with the environment they are operating in (ie. take a PNS neuron and put in in CNS conditions and it will regenerate more like a CNS neuron). That's my recollection without breaking out my cellular neuro book. Why are you using an optic nerve as a model, is it particularly suited for the research somehow? Psychedelic research is really interesting. I hope after some marijuana legalization in the U.S. that there is a subsequent movement for psychedelic usage in the medical field (and, eventually, some decriminalization of psychedelics for recreational use as well). MAPS is a very promising program, but rather limited by funding right now [ http://www.maps.org/ ] . I'm currently picking up some clinic hours and a few classes at a community college before I apply for a Physician's Assistant program. I've been encouraged a few times to try for an MD/PhD program, but I'm afraid I don't have the wherewithal for another 6+ years of school and training to become a doctor. And in a research aspect, while I found lab work interesting and generally rewarding, it is very draining. Thus far, I expect clinical work to be more my speed, and a PA program will have me in the workforce in ~3 years from today.
Your knowledge about axon regeneration is similar to mine when I started 2 months ago :) There are several differences. The scar tissue (glial scar) is the first. We have axon repellents in the CNS that we have to overcome, to do that we have to look for dis inhibitory effects when gathering pathways, which is also part of our work. Typically this is done by playing cells on myelin for example. Another problem we face is the growth comes of regenerating axons. Their dynamics in forming actin filaments differed in PNS vs CNS. This might be due to upstream signaling differences. Lack of specific proteins that are only expressed in PNS neurons. This brings me to the third difference, the regenerative capacity of CNS neurons is "lost" during development. This is due to blockage of regenerative signaling pathways. In the past 10 years a lot of studies have examined the pathways that change during development in neurons and got to some pathways that seems to play an import role like the PI3K->Akt->mTOR/GSK3 pathways which is the focus of our studies. The optic nerve is interesting because it's part of the CNS and it's easy to examine. Through performing a crush right behind the eye (beginning of the optic nerve) and subsequent excision of the whole nerve and staining the axons we can assess how well the axons regenerated after specific treatments. Funding is the main problem with psychedelic research. It is still a "taboo" subject and people still don't believe in those substances as medicine or good tools for research. Hopefully it will change with time... Research is indeed a draining work, specially when things do not turn out as you wanted. On the other side, you keep learning. It never gets boring :) I wish you the best of much with your plans. Applications sent yet?