Stress: Of Rats and Men

Immobilization is one technique used to put stress on a rat (1). Since it is difficult to get a rat model of schizophrenia, rats are often put under stress and tested. The drug methamphetamine has been used to simulate schizophrenia rats, but this is speculative.

"Despite the reduced plasma levels, corresponding brain concentrations of many large neutral amino acids (LNAAs) were increased (tryptophan, phenylalanine, valine, leucine, and isoleucine). Brain concentrations of tyrosine and the other amino acids measured were unaltered." (1)

Thus stress on the rat caused an increase in certain brain amino acids. Since schizophrenia is like a perpetual state of stress, this suggests that certain amino acids may also flood the brain cells in schizophrenia.

An Animal Model of Depression?

The same London group did a lot of experiments (2, 3).

"As failure to adapt to repeated stress is an animal model of depression, results as a whole suggest that increased corticoid levels and decreased 5-HT functional activity may have a role in the development of the illness and its greater incidence in women."

Haleem DJ, Kennett G, Curzon G.

Department of Neurochemistry, Institute of Neurology, London, U.K.

This quote is from Ref. 3.

Amphetamine

Amphetamine has been considered a model for schizophrenia. In other words, it produces a model psychosis.

"Despite the increase in brain tryptophan caused by amphetamine, this drug had relatively little concurrent effect on 5HT synthesis." Fernando JC, Curzon G. (5)

This throws cold water on the serotonin theory for schizophrenia, but it strengthens the theory of tryptophan itself causing schizophrenia. This is a theory that I favor.

Hyperactive Rats

Rats were made hyperactive by treatment with tryptophan and a MAO inhibitor (5, 6). Again this appears to support a role for tryptophan itself, and the role is an adverse one. Excessive brain tryptophan may cause mental illness. It does not say much for MAO inhibitors. Rather it suggests that a toxic amine may be involved. The MAOI is preserving the toxic amine.

Also this throws very cold water on the serotonin theory. Both treatments increase brain serotonin. According to the theory, serotonin is supposed to be low in schizophrenia. The only difference was the the British were using stressed rats as a model for depression, not schizophrenia. Depression was a more popular diagnosis in Britain at the time.

Serotonin Depletion

Serotonin depletion experiments have been done on rats.

"Depletion of telencephalic serotonin (5-HT) content by medical forebrain bundle lesions, which interrupt the ascending serotonergic pathways or by DL-p-chlorophenylalanine produces an increased sensitivity to pain as measured by the flinch-jump, stabilimetric, or hot-plate methods. Examination of the effects of a number of other lesions and drugs indicated that dopamine, norepinephrine and acetylcholine are not involved in pain sensitivity." Harvey JA, Schlosberg AJ, Yunger LM. (7)

This suggests that serotonin inhibits pain. This appears to throw even more cold water on the serotonin theory for schizophrenia. Supposedly the serotonin is supposed to be low in schizophrenia, but that theory was based on naval contemplation rather than on actual measurements. The theory has survived because it is advocated by the drug companies to justify SSRIs (selective serotonin reuptake inhibitors), which can increase serotonin, sometimes to a pathological degree causing the serotonin syndrome.

Diet

"Previous work from our laboratory points to plasma free tryptophan being a useful predictor of brain tryptophan concentration in many circumstances. Other work, in particular various studies on the acute effects of food intake, has emphasized the roles of plasma total tryptophan and of plasma large neutral amino acids that compete with tryptophan for transport to the brain." Sarna GS, Kantamaneni BD, Curzon G. (9)

This British group has done a tremendous amount of work on tryptophan. Giving carbohydrates to the rats caused a rise in brain tryptophan. This was caused by a lowering of amino acids in the plasma that complete with tryptophan. Insulin caused the lowering of the competing large neutral amino acids.

Psychiatric Drugs

Unfortunately there has been toxicity from psychiatric drugs (11, 12, 13).

"Results suggest a relationship between haloperidol dose and toxic effects on the liver, and they indicate that a high dose of haloperidol may result in irreversible liver damage." (13)

Halici Z, Dursun H, Keles ON, Odaci E, Suleyman H, Aydin N, Cadirci E, Kalkan Y, Unal B.

Department of Pharmacology, Ataturk University School of Medicine, 25240, Erzurum, Turkey.

Russian Research on Stress

The Russians have also used stressed rats as a model for schizophrenia (14). Using the electron microscope they studied the brains of rats who had been stressed by hyperthermia. This means that they heated up the rats and then killed them. This was not kind, but the findings were striking. They found acute swelling of neurons in all parts of the brain.

"At the ultrastructural level these phenomena were characterized by an increase in the size of the bodies and nuclei of neurons, complete dissociation of polysomes, swelling of some cisterns of the endoplasmatic reticulum and perinuclear space, and destruction of the mitochondria of apical processes." (14)

Conclusions

The Russian research was consistent with the British research. The British found a flooding of the brain with amino acids. This would explain the swelling of the neurons, the swelling of cisternae of the ER, and the destruction of the mitochondria. The Russians felt that this pathology was similar to that found in schizophrenia.

The only difference was the the British were using stressed rats as a model for depression, not schizophrenia. Depression was a more popular diagnosis in Britain at the time. In Russia most mental diseases were considered variations on schizophrenia. They divided the various types of mental disease into classifications of schizophrenia. In other words, schizophrenia was considered many different diseases, much like cancer and mental retardation.

More information on depression is given in Ref. 15. More information on schizophrenia is given in Ref. 16. Both 15 and 16 are available free full text on the Internet.

References

1. Immobilization decreases amino acid concentrations in plasma but maintains or increases them in brain. Kennett GA, Curzon G, Hunt A, Patel AJ. J Neurochem. 1986 Jan;46(1):208-12.

2. Brain tryptophan. Normal and disturbed control. Curzon G. Adv Exp Med Biol. 1996;398:27-34. Review.

3. Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesis. Haleem DJ, Kennett G, Curzon G. Brain Res. 1988 Aug 23;458(2):339-47.

4. Effect of d-amphetamine on tryptophan and other aromatic amino acids in brain. Fernando JC, Curzon G. Eur J Pharmacol. 1978 Jun 15;49(4):339-49.

5. Grahame-Smith DG. Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J Neurochem. 1971 Jun;18(6):1053-1066.

6. Role of tryptamine in the behavioural changes caused by a monoamine oxidase inhibitor and L-tryptophan [proceedings]. Curzon G, Marsden CA. Br J Pharmacol. 1977 Jun;60(2):307P-308P.

7. Harvey JA, Schlosberg AJ, Yunger LM. Behavioral correlates of serotonin depletion. Fed Proc. 1975 Aug;34(9):1796-1801.

8. Koe BK, Weissman A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther. 1966 Dec;154(3):499-516.

9. J Neurochem. 1985 May;44(5):1575-80. Variables influencing the effect of a meal on brain tryptophan.Sarna GS, Kantamaneni BD, Curzon G.

10. Psychol Med. 1979 Aug;9(3):457-63. Tryptophan disposition in psychiatric patients before and after stress.Curzon G, Kantamaneni BD, Lader MH, Greenwood MH.

11. Green tea modulates reserpine toxicity in animal models. Al-Bloushi S, Safer AM, Afzal M, Mousa SA. J Toxicol Sci. 2009 Feb;34(1):77-87.

12. In vivo observations of chlorpromazine ocular deposits in a patient on long-term chlorpromazine therapy. Razeghinejad MR, Nowroozzadeh MH, Zamani M, Amini N. Clin Experiment Ophthalmol. 2008 Aug;36(6):560-3.

13. Naunyn Schmiedebergs Arch Pharmacol. 2009 Mar;379(3):253-61. Epub 2008 Oct 21. Effect of chronic treatment of haloperidol on the rat liver: a stereological and histopathological study. Halici Z, Dursun H, Keles ON, Odaci E, Suleyman H, Aydin N, Cadirci E, Kalkan Y, Unal B.

14. Zh Nevropatol Psikhiatr Im S S Korsakova. 1985;85(7):1016-20.[Ultrastructural analysis of the phenomenon of acute neuronal swelling]
15. www.associatedcontent.com/article/2255365/depression_research_including_treatments.html

16. www.associatedcontent.com/article/2270615/magnetic_resonance_spectroscopy_studies.html