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Potential Schizophrenia 'Switch' Found

posted by martyb on Wednesday September 21 2016, @05:49PM   Printer-friendly

Phoenix666 writes:

Researchers at Vanderbilt University Medical Center have discovered a key mechanism that explains how compounds they're developing can suppress schizophrenia-like symptoms in mice without side effects.

On the basis of this discovery, reported this month in the journal Neuron, "we now have [a] much stronger understanding of the therapeutic potential and mechanism of action of compounds that are advancing to clinical development," said P. Jeffrey Conn, Ph.D., director of the Vanderbilt Center for Neuroscience Drug Discovery.

An estimated 3 million Americans have schizophrenia, which is associated with excessive amounts of the neurotransmitter dopamine in a part of the forebrain called the striatum.

Current medications reduce hallucinations and delusions, the hallmark of schizophrenia, by blocking dopamine receptors. But because they also block dopamine receptors in the cerebral cortex, they can worsen cognitive difficulties.

Daniel J. Foster, Jermaine M. Wilson, Daniel H. Remke, M. Suhaib Mahmood, M. Jashim Uddin, Jürgen Wess, Sachin Patel, Lawrence J. Marnett, Colleen M. Niswender, Carrie K. Jones, Zixiu Xiang, Craig W. Lindsley, Jerri M. Rook, P. Jeffrey Conn. Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release. Neuron, 2016; DOI: 10.1016/j.neuron.2016.08.017

Good news for sufferers.

Original Submission

 
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  • (Score: 2) by aristarchus on Thursday September 22 2016, @05:13AM

    by aristarchus (2645) on Thursday September 22 2016, @05:13AM (#405034) Journal

    So far, there is not a single comment that addresses the science or the application of the science. I expect more of my fellow Soylentils, and since this is not one of my many areas of expertise, I call upon anyone who has such to chip in. No, jmorris, not you! Yes, Francis, we know you do not know something about this as well. And no, Runaway, just no. Nothing to do with hillbilly cable news and talk radio, or muslims, so just stay the hell away from it, please. So, anyone? Bueller?

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  • (Score: 2) by JeanCroix on Friday September 23 2016, @03:48PM

    by JeanCroix (573) on Friday September 23 2016, @03:48PM (#405577)
    I have the distinct feeling that this particular field of science is rather poorly represented amongst the SN userbase. Or, if there are biotech/psych people around, maybe they are keeping quiet so as to not get dogpiled by armchair experts.

    • (Score: 1) by sbgen on Friday September 23 2016, @05:15PM

      by sbgen (1302) on Friday September 23 2016, @05:15PM (#405623)

      Perhaps here is another thing to consider - time needed. It took me about an hour to translate what I read in the paper into plain English and type the response below. I know it still sounds complicated but English is not my first language and the work is technical. And, the paper is solidly pay walled - I can get it in the lab only. Here are multiple curses for closed publication model [.....]

      --
      Warning: Not a computer expert, but got to use it. Yes, my kind does exist.

  • (Score: 2, Informative) by sbgen on Friday September 23 2016, @04:40PM

    by sbgen (1302) on Friday September 23 2016, @04:40PM (#405601)
    OK, artistarchus, I will try to give you some information on this; its only fair since I have enjoyed some of your comments in the past and I know a thing or two on one part of this kind of research. The science in this paper is understanding the precise mechanism by which a particular compound acts to alleviate some of the schizophrenia (SZ) symptoms. And it tells where exactly this is happening in brain. The compound/s the authors have been working on for a while activate M4-muscarinic receptors specifically in spiny projection of neurons, a small subpopulation of neurons in striatum, a structure that is part of the forebrain. It was already shown by another group in 2008 (Shekhar et al, Am J Psyhiatry, 10.1176/appi.ajp.2008.06091591) that compounds that activate these receptors have antipsychotic effects. However, such compounds were mostly non-selective and blocked dopamine receptors in entire fore-brain and hence lead to serious side effects. Authors of the current paper, and some other groups as well, subsequently identified compounds that were very specific to M4-receptors. As is the norm this worked out well for rodents (notarized statements from said rodents not available) but the actual mechanism of action was not understood. Now, this paper is the next step in the research. Here authors show that the selective compounds they have act through a sub-population of neurons within a sub-structure of the fore-brain. In the process they also figured out that these compounds do not block dopamine receptors directly but block the release of dopamine itself. Moreover, this is done via a cannabinoid receptor CB2. It had been generally believed in literature that this was not possible. So another one of the long held beliefs falls in the process. You also asked about the application of the science. This paper narrows down where M4 receptors act to reduce psychotic effects to a very small region - a subpopulation of cells. It also clearly shows how this happens. It will enable developing highly targeted compounds for treating psychotic symptoms with minimal side effects. Note I did not say it will cure SZ; I did not say side effects will not occur. The paper advanced science to another step closer to treatment of some symptoms in psychiatric disorders. Next steps should occur much faster and then the time will become a function of the accepted legal procedures (FDA procedures). Tiny steps, but approaching some tangible goals quicker than before. Thanks to phoenix66 for posting with DOI.
    --
    Warning: Not a computer expert, but got to use it. Yes, my kind does exist.