Psychology in the News

April 22, 2009

Models of Schizophrenia

Filed under: dopamine, drugs, mental illness — intro2psych @ 10:24 pm

By Alex Herman

crazy mouse moon by indi the thirstyfish

crazy mouse moon by indi the thirstyfish

LSD and other psychoactive drugs such as ketamine, psilocybin, DMT, and peyote (mescaline) have for many years held the interest of researchers and scientists throughout the world due to the striking effects that they have on the brain functions and behavior of many mammals.  Psychiatric research in particular was initially drawn to the use of LSD (Lysergic acid diethylamide) as a drug that could produce model schizophrenia in test subjects and patients.  There is a long history of psychedelics research correlated with schizophrenia ever since LSD and its counterparts proliferated in use during the 1960’s and 70’s (Snyder et al. 1974).  In the mid 70’s, certain research conducted by Bowers and Freedman highlighted surprising similarities between the states of some early schizophrenic patients and the effects of psychedelic drugs (Snyder et al. 1974).  Apparently, it was in the acute schizophrenic breakdowns of new patients that the researchers observed effects such as transcendence to new modes of perception and creativity.  Also observed were experiences of both intense dread and elation, attitudes that are frequently alternated between in patients experiencing a psychedelic ‘trip’.

The relationships between psychedelics and schizophrenia are still being explored in today’s research, but now researchers are focusing in on the use of psychedelics as a model to test possible treatments for this debilitating mental disease.  In early studies regarding neurotransmitters and schizophrenia, it was believed to be the abnormal levels and fluctuations of the neurotransmitters serotonin and dopamine that were primarily responsible for the diseases’ dramatic effects, but recent research on mice is uncovering a different culprit acting in the synapses of test subjects: the neurotransmitter glutamate.  The so-called serotonin-glutamate complexes are under intense study made possible by the dosing of lab mice with nominal amounts of LSD and ketamine.  Recent studies done by Stuart Sealfon and other researchers at the Mount Sinai School of Medicine in New York indicate that mice, when dosed with LSD, will experience behavior closely associated with schizophrenia in humans, due to uncontrolled regulation of serotonin receptors in neurons.  These behaviors, however, are canceled out when a drug altering the glutamate receptors is given to the mice, indicating that glutamate transport and reception plays a much more important role in schizophrenia than we had originally thought.

In even more recent studies using the behavior of mice on psychoactives to model schizophrenia, findings suggest that the condition may actually be a result of glutamate hyperactivity as opposed to the original belief in hypoactivity (too much vs. too little activity).  In this research, the lab rats used were genetically altered to ‘knockout’ (delete) the gene for the glutamate transporter EAAT1.  This transporter has been “implicated in schizophrenia” as it is important in the removal of glutamate from in between cells and synapses.  These ‘knockout’ mice were then given the NMDA glutamate receptor antagonist MK-801, which is a drug that stimulates an increase in the release of glutamate into the synaptic space.  With an increase in glutamate and no way for the mice to regulate its distribution and transport, the effects produced in the behavior of the mice were striking.  The mice displayed distinctly schizophrenic symptoms including hyperactivity, symptoms that have been closely associated with rats dosed with LSD and ketamine.  It is true that these symptoms still do not make lab rats a paragon for modeling schizophrenia, especially in terms of the cognitive effects in humans, but they can still help to lead researchers towards new, more effective treatments.

The end game to all this recent research is that we are now on the path to finding more effective and useful treatments to combat the horrible effects of schizophrenia.  The effects seen in the EAAT1 knockout mice can be helped through the use of glutamate-targeting drugs, and medicines are currently being developed of this persuasion for use as effective anti-psychotic treatments.  The interplay between psychoactives, neurotransmitters, and schizophrenia is clearly helping to move medical research forward on a complex and debilitating mental disease.

References

Elsevier (2008, October 29). Glutamate: Too Much Of A Good Thing In Schizophrenia?. ScienceDaily. Retrieved March 1, 2009, from http://www.sciencedaily.com­ /releases/2008/10/081027115427.htm

Rodvelt, K.R., Kracke, G.R., Schachtman, T.R., & Miller, D.K. (2008). Ketamine induces hyperactivity in rats and hypersensitivity to nicotine in rat striatal slices . Pharmacology Biochemistry and Behavior, 91, 71-76.

Snyder, S.H., Banerjee, S.P., & Yamamura, H.I. (1974). Drugs, neurotransmitters, and schizophrenia. Science. 184, 1243-1253.

Sealfon, Stuart (2008, February 25). LSD reveals schizophrenia treatment. Retrieved March 1, 2009, from news.com.au Web site: http://www.news.com.au/story/0,23599,23270344-23109,00.html

Myers, D.G. (2007). Psychology: Eighth edition in modules. New York, NY: Worth Publishers.

11 Comments »

  1. The similarity between the cultured neural environment and the drugged mice’s behaviors with those of human patients with schizophrenia, seems like a good correlation, but I am not sure that the behavior alone, especially when it must be measured subjectively, is enough to direct the research to think that a direct chemical correlation exists. Is there more on the operation of the psychodelics on schizophrenic patients? It might make sense to see a reduced or subdued effect there to reinforce the correlation.

    Comment by Joshua Klein — April 22, 2009 @ 11:01 pm

  2. Focus on drugs that help fix brain chemical imbalances is obviously important for diseases like schizophrenia. I’d guess that if a cure is ever found, it will involve neurotransmitter control in some way or another.

    However, I’m also interested in easier remedies. Recall from class that treatment of Schizophrenia is most effective when it is combined with cognitive and family therapy. But what about physical therapy? Can running on a treadmill help balance brain chemicals? I would guess that a “runner’s high” could be a great way to make a suffering patient feel better, if not heal a bit.

    Or how about music and dance therapy? If it helps stroke victims by increasing brain blood flow, could it help schizophrenia patients too? Or would too much wild activity exacerbate symptoms of agitation? Just some thoughts.

    Comment by Alex Middeleer — April 25, 2009 @ 12:57 pm

  3. I think that, ultimately, genetic studies (such as the glutamate transporter EAAT1 gene knockout in rats) will be key to fully understanding the origins of schizophrenia. While these latest rounds of research seem to indicate that glutamate activity plays a more important role than serotonin in developing schizophrenia’s symptoms, I think it is more likely the interaction of these two is what leads to diagnosable schizophrenia.

    Regarding genetic theories of mental illness, one new theory put forth by Bernard Crespi suggests that mental illness results from bias towards one parent’s genes, and that autism and schizophrenia are at opposite ends of the spectrum. The theory says that genetic bias towards the father leads to autism and towards the mother leads to schizophrenia and other mood disorders. While people with schizophrenia have an “over-sensitive sense of self”, including feelings they are always being watched and plotted against, people with autism often lack social awareness and associated behaviors. In this way, these and other mental illnesses may have similar causes and so finding a cure for one may mean finding a cure for many.

    Comment by Will Jobs — April 26, 2009 @ 3:18 pm

  4. I think you might be interested in my blog. For me, going on a very low glutamate diet ends my bipolar disorder symptoms. Completely. Two years, no drugs, no relapse.

    http://glutamateandhealth.wordpress.com/

    Comment by Christian — April 27, 2009 @ 8:09 pm

  5. During our class discussion, the dopamine and glutamate theories for the cause of schizophrenia seemed to have been depicted as rival ideas, so what interested me about this post was the mention of the “so-called serotonin-glutamate complexes.” A recent review co-written by Mt. Sinai researcher Sealfon discussed findings on antipsychotic drugs based on PCP and LSD induced schizophrenia models (Gonzalez-Maseo and Sealfon, 2009). They found that atypical antipsychotic drugs which targeted structures in either serotonin or glutamate pathways were both successful in controlling LSD induced symptoms of schizophrenia. Sealfon identified the serotonin-glutamate receptor complex that Alex mentioned as a possible target for both the psychedelic and antipsychotic drugs, a discovery which might lead to a unification of the serotonin and glutamate hypotheses of schizophrenia. The researchers at Mt. Sinai seem to believe that the key to better understanding this disorder is taking into account all the factors which may be involved. Sealfon’s goals are oriented towards taking all these theories into consideration when studying the possible causes and treatments for psychotic disorders. He believes that the next step in schizophrenia research is to relate the mostly dominant dopamine hypothesis of schizophrenia with the much newer serotonin-glutamate hypothesis. Based on his previous success with LSD and PCP’s ability to mimic psychotic disorders, he believes that continued attention to these drugs will facilitate further development in therapies for schizophrenia.

    References

    Gonzalez –Maseo, J., Sealfon, S.C. (2009). Psychedelics and schizophrenia. Trends in Neurosciences, 32 (4), 225- 232.

    Sealfon, Stuart (2008, February 25). LSD reveals schizophrenia treatment. Retrieved April 26, 2009, from news.com.au Web site: http://www.news.com.au/story/0,23599,23270344-23109,00.html

    Comment by Julia Ding — April 28, 2009 @ 4:04 am

  6. It is very interesting to think that pharmaceuticals can be both abused to horrifying results or used to help treat and model diseases. Corlet, Honey and Fletcher (2007) propose that Ketamine, an NMDA receptor antagonist, used in medicine can serve as a model for the evolution of symptoms in schizophrenia. One symptom is the presences of delusions that are formed when a patient attempts to rationalize associations between stimuli by signifying irrelevant details and perceptions. The researchers propose that delusion formation is the result of an associative learning process and such a process is based on a prediction signaling error. Prediction errors occur when an organism expects an incorrect occurrence, serving as a signaling tool that helps the organism associate objects to actions. The issue is that research suggests dopamine and glutamate are essential to prediction signaling that schizophrenia (modeled by Ketamine) affect these neurotransmitters, possibly leading to delusions.
    Reference:
    Corlett, P.R., Honey, G.D., & Fletcher, P.C. (2007). From prediction error to psychosis: Ketamine as a pharmacological model of delusions. Journal of Psychopharmacology, 21, 238-252. (Retrieved April 30th, 2009 from http://jop.sagepub.com/cgi/reprint/21/3/238)

    Comment by Jason Adler — April 30, 2009 @ 6:25 pm

  7. Schizophrenia is an extremely complex brain disorder that can effect the lives of those with the disorder to the point where their brains can no longer function properly. Along with the suggestion that hyperactive glutamate activity instead of hypoactive glutamate activity could cause schizophrenia, some scientists have proposed a similar hypothesis with a twist. In an article published in the Journal Neurotoxicity Research, it is believed that along with a hyperactivity of glutamate one would need a hyperactivity of dopamine as well to cause schizophrenia. It is believed that the hyperactivity of glutamate that is produced by the NMDA receptor blockade is dependent upon the stimulation of the dopamine D3 receptor, (http://www.springerlink.com/content/982r3n304441pn53/?p=fdc8bc2754c848ef8b13b2d036a2afba&pi=7). Therefore is could be a combination of too much glutamate and too much dopamine that interact in order to cause schizophrenia.

    Comment by Shannon Fleming — May 4, 2009 @ 2:02 pm

  8. Though Albert Hoffman (the creator of LSD) may have intended LSD to model psychosis in order to study it, it is prominently used as a recreational drug today. However back in the 1970s it was used in a number of experiments to see what effects it would have. Surprisingly they found that it could be used to treat certain singular problems, provided the subject did not have a predisposition to psychosis. It served as a painkiller that was as strong as other painkillers but lasted longer and was also used in treating alcoholism, phobias and other drug addictions.

    LSD was rather effective at treating alcoholism. Many who were told to quit drinking while experiencing the effects of LSD quit within a year (http://books.google.com/books?id=ASoDAAAAMBAJ&pg=PA60&dq=%22non+cop+non+hippie%22&lr=&client=firefox#PPA62,M1). The scientists did not know why this occurred but it is rather interesting.

    Furthermore I find it extremely interesting that psychosis and schizophrenia can be modeled for a short time from a man-made substance. Since we know that LSD works by increasing glutamate production scientists are seeing that if adding a substance that blocks the glutamate receptor can stop hallucinations as it does when combined with LSD (http://www.scientificamerican.com/podcast/episode.cfm?id=67242F1C-FBD3-BC26-FA8585B8F16D051F). This technology could then be combined to cure other similar diseases. If we can cancel out the effects of LSD safely then we could possibly use LSD as a medicine as they did back in the 1960s and 1970s and then prescribe the counter-drug to alleviate the hallucinations and other side effects.

    Comment by Nick Johnson — May 4, 2009 @ 5:20 pm

  9. What found particularly interesting about this article was the research portion that focused on the seratonin-glutamate activity. I am not sure if it was mentioned in the lecture but the affects of glutamate on schizophrenia were one of the primary fears involved with Monosodium Glutamate or MSG. MSG which is a food additive found in a lot of processed food. The primary scare of MSG was the fact that when dissolved, it formed free Na+ and glutamate ions. The glutamate ions where thought to affect brain activity and thus, induce symptoms associated with schizophrenia. However, recent studies have shown that the glutamate ions from MSG do not have any adverse affects on the brain since they are not properly absorbed in digestion. However, MSG has been eternally labeled as a “bad” ingredient, prompting restaurants to advertise “No MSG.” Even so, this advertisement it self is controversial, not taking into account the glutamic acid contents of the original food themselves. One can say that there is a social stereotype and prejudice against MSG based on negative assumptions.

    Comment by Aaron Suzuka — May 5, 2009 @ 9:47 am

  10. This was an interesting perspective on the causes of schizophrenia, which could in turn lead to more effective treatments. However, although glutamate probably does play a large role in the onset of schizophrenia, it is highly unlikely that it is the only contributing factor.

    In a recent Science Daily article, (http://www.sciencedaily.com/releases/2009/05/090506094218.htm), Isoform 3.1, a version of the KCNH2 potassium channel was also implicated as one cause of the disorganized brain function typical of schizophrenics. Apparently, Isoform 3.1 helps control neural firing that supports higher mental functions unique to primates including thought and memory. According to the article, the chemical was found at levels 2.5 times higher than normal in the hippocampuses of schizophrenic patients. Despite the important function of Isoform 3.1, it is thought that in excess, it can lead to “runaway circuit activity and inefficient information processing”. If scientists could effectively stem the excessive amounts of Isoform 3.1, it could lead to less intrusive, and debilitating treatments than those currently available.

    Comment by Victoria Velasco — May 11, 2009 @ 12:34 pm


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