Quantum Biosystems | 2011 | Vol 3 | Issue 1 | Page 12- 18 Massimo Cocchi et al

12

Opinion And Perspectives

Biological and AnthropologicalExistential Hypothesis on Depression

Massimo Cocchi*, 1Lucio Tonello, 1Fabio Gabrielli, Massimo Pregnolato
Abstract

This paper focuses on the relationship between platelets and neurons by relating the membrane viscosity with the concentrations of the neurotransmitter serotonin. The action of serotonin being mediated by the platelet membrane arachidonic acid concentration and by its exchange with the neuron membrane in the brain. The hypothesis that some diseases such as scleroderma and inflammatory bowel syndrome develop in relation to pathological features of cerebral and enteric neurons, in coexistence of depressive disorders, is here considered. In this context, depression is seen as the original structure of our existence in the world, both from a biological point of view that existential. .
Key Words: Brain Neuron, Enteric Neuron, Platelets, Membrane Viscosity, Protein

Gs, Tubulin, Serotonin, Depression, Artificial Neural Network, Scleroderma, Inflammatory Bowel Disease, Human finitude, Original structure.
Quantum Biosystems 2011; 3 (1): 12-18

Introduction Because of some characteristics of psychiatric diagnosis ambiguity, it seems nowadays necessary to seek new avenues such as the quantitative approach in psychiatry and the quantum model of mind, brain and consciousness. However, there is an open question: how to connect these disciplines with the experimentally psychiatric world? Many molecular theories have been proposed such as connection between the function of the cytoskeleton (Woolf, 2010) and Gs proteins in lipid membrane microdomains (Donati, 2008).

Corresponding author: Massimo Cocchi Address: *Institute "Paolo Sotgiu: Quantitative and Evolutionary Psychiatry and Cardiology, Faculty of Veterinary Medicine, University of Bologna, Faculty of Human Sciences, L.U.de.S University, Lugano, Switzerland, Quantumbiolab Department of Drug Sciences University of Pavia e-mail: massimo.cocchi@unibo.it Received January 13, 2011. Revised June 24, 2011. Accepted 29 June, 2011

Links to the viscosity of the cell membrane of neurons and platelets (Tonello, 2010) and their likely influence on the biomolecular complex intracellular, which is the interactome (defined as "the whole range of molecular interactions that occur in an organism and allow the cascade of regulatory molecules including the mechanism of action of enzymes and metabolic reactions") are often neglected in the literature (Cocchi, 2010a). In 1980, Heron (Heron, 1980) described the correlation between membrane viscosity and the affinity of serotonin receptors. We hypothesize that this condition could promote the onset and/or the modulation of psychiatric disorders. After 30 years it has been possible to demonstrate, using a mathematical model, that platelet membrane viscosity can affect the type and intensity of psychiatric disorder and that the high concentration of arachidonic acid is the main element of criticality (Cocchi, 2009a,b).

ISSN 1970-223X

www.quantumbiosystems.org

Quantum Biosystems | 2011 | Vol 3 | Issue 1 | Page 12- 18 Massimo Cocchi et al

13

These experimental findings find support in the important work of Heron (1980) and Samuel (1985) who, however, does not explain the relationship among the viscosity of platelet and neuron membranes and serotonin concentration. The viscosity of the membrane was then taken up by Donati et al. (2008) regarding the modification of Gs in the brain of suicide because of depression, compared with subjects who died from other causes. The hypothesis of the link between platelets, neurons and serotonin, made by Cocchi et al. (2010a) is that in depressive disorder, the high concentration of arachidonic acid in the platelets membranes (Cocchi, 2008) and the relative decrease in viscosity causes a defect in serotonin re-uptake, thereby reducing the concentration within the platelets (Cocchi, 2010a). The high concentration of arachidonic acid in platelets membranes will prevent the mutual exchange with the brain neurons membranes (Cocchi, 2009a,b). The neurons arachidonic acid concentration tends to increase because the brain receives arachidonic acid from other sources. A significant reduction in viscosity of neuronal membrane, would lead to a significant reduction of serotonin reuptake and receptors binding, a phenomenon at the base of the altered serotonin system. This would explain the similarity of common characteristics

between neurons and platelets in depressive disorder (Takahashi, 1976; Edwards, 1978; Marangos, 1979; Kim, 1982; Rotman, 1983; Dreux, 1985; WirzJustice, 1988; Camacho, 2000; Plein, 2001; Maurer-Spurej, 2007). The research background on Depression:

The use of a Self Organizing Map (SOM) has identified three fatty acids of the platelet lipid membrane as markers (Cocchi, 2008; 2010b). Figure 1
The position of each subject, a point on the map that reflects all the three fatty acids isolated by the SOM, was further clarified by calculating a coefficient, B2, using the melting point and the molecular weight of each of the three fatty acids which represent the platelets membrane fatty acids majority (Cocchi, 2010b,c).

Calculation of B2 index:

ISSN 1970-223X

www.quantumbiosystems.org

Quantum Biosystems | 2011 | Vol 3 | Issue 1 | Page 12- 18 Massimo Cocchi et al

14

The distribution of the B2 coefficient (that gives an assessment of viscosity) shows that the viscosity is increasing from right to left.

This confirms the lower viscosity, then the higher fluidity, of platelet membranes of depressed subjects with respect to the normal ones.

In formulating the molecular hypothesis of depression (Cocchi, 2010a), a first step was to find that the entire path involves the application of both a linear and a non linear mathematical models, that could lead, according to Hameroff and Penrose from quantum computations in tubulins to the neuro correlate of consciousness (Orch-OR Theory) (Hameroff, 1996, 2009; Penrose, 2011). According with Heron (1980) and by studying the transfer of arachidonic acid (Cocchi, 2009a,b), the link between enterochromaffin cells, platelets and neurons in depressive disorder, and perhaps in other conditions, seems plausible (Figure 2a,b). As a consequence of the experimental data on the biochemical characterisation of platelet fatty acids in depression and in scleroderma (Cocchi, 2010a,b), is notable
ISSN 1970-223X

the fact that scleroderma could be a consequence of depression. In fact, all people suffering of scleroderma are classified as depressed but none of the depressive subjects investigated had clinical signs of scleroderma. Figure 3 describe the biochemical similarities between scleroderma and depression and among young people (normal cases) and Morphea (Cocchi, 2010a), identified by the Self Organizing Map (SOM) for depression (Cocchi, 2008). Therefore, also the hypothesis of a unidirectional link between depression and inflammatory bowel syndrome might be plausible, given the high percentage, as in scleroderma, of the incidence of depression (Kurina, 2001; Graff, 2009).

www.quantumbiosystems.org

Quantum Biosystems | 2011 | Vol 3 | Issue 1 | Page 12- 18 Massimo Cocchi et al

15

Brain-Gut axis It is known that the aspects embracing mood disorders and inflammatory bowel disease involves, in directions, the braingut axis (Collins, 2009) and the relationship among enteric neurons, serotonin, functional aspects of the intestine and microbioma (Simon, 1990; Chen, 2001; Coates, 2004; Michel, 2005; Kim, 2009; Kunze, 2009; Sikander, 2009; Bertrand, 2000). Collins and Bercik (2009) have attempted to show how changes in the microbioma are involved in the pathogenesis of mood disorders, noting the possibility of a parallelism between microbioma and bowel function but found difficulties in establish the primary liabilities. The serotonin pathway, as was previously mentioned, is affected by changes in membrane viscosity, involving platelets and brain neurons. If this phenomenon is also attributable to the enteric neuron, we can think that similar molecular changes occur, determining the conditions that activate PKC, PKA, Adenyl Cyclase and AMPc resulting in modification of ion flux (Gaginella, 1998; Alberts, 1998). If the molecular changes in neurons, involving serotonin, are linked to mood disorders and if these changes are also detectable in enteric neuron, one might reasonably expect the onset of pathological

states of inflammation in the intestine, through a mechanism very similarly as described for depression, Figure 4.

If all the depressed dont have inflammatory syndromes, as in depression for scleroderma, it is questionable whether it is possible to connect the complex mechanism of depression to the onset of inflammatory bowel disease and not vice versa. In other words, it would be reasonable to think that depression could be the possible cause of very serious diseases.

ISSN 1970-223X

www.quantumbiosystems.org

Quantum Biosystems | 2011 | Vol 3 | Issue 1 | Page 12- 18 Massimo Cocchi et al

16

Inflammatory bowel diseases, eg, within the different frameworks of gravity that they may show, can be cause or effect of depression? We believe that depression may be defined as a biological click and, as a consequence, an anthropologicalcultural one, because, in our opinion, biology and culture are two continuing worlds. As Heidegger suggests, we can synthesize our opinion like this: depression is the original ontological structure of human life in all its ontics, i.e. historical-cultural and biographical expressions, from a biological and anthropological-existential point of view. Finally, depression could be observed as a fundamental interpretation key of human finiteness and could therefore explain the precariousness of human life, at the biological and cultural level, according to Figure 4. Conclusion The enteric neuron may undergo the same molecular changes of the brain neuron and activate a similar molecular cascade. In their autonomy, both structures, the brain, for the brain neuron, and intestine for the enteric neuron, appear to be connected by a thin line so that, in inflammatory bowel diseases there is very high percentage of mood disorders. However, from the plausible and sustainable evidence obtained, it seems safe to assume that depression is the phenomenon under which the inflammatory bowel disease develops, that is, the altered brain neuron function seems to precede those of enteric neuron. The serotonin route, from enterochromaffin cells to platelets, in its relations with the viscosity of the membrane that influences its receptor binding, might be the phenomenon that precedes the occurrence of changes in the enteric neurons. Therefore, should be the occurrence of the phenomenon of depression and the related condition of decreased individual functional capacity, which lead to the onset of inflammatory phenomena. The
ISSN 1970-223X

membrane viscosity, together with serotonin receptors and molecular changes in brain neurons, could be associated to the biological domain of enteric neuron to represent the conditions that induce the inflammatory bowel syndromes. Brain and Enteric Neurons represent two domains with their areas of influence, linked by an essential and common molecular pathway. The cell membrane, in its characteristics of viscosity, might be the central issue to which future researches will focus to better understand the complex phenomena that link serotonin and its transport in the dynamics of relationship with bi-directionally brain-gut axis. References
Alberts B. (1998) The cell as a collection of protein machines: preparing the next generation of molecular biologists. Cell. 92: 291-294. Bertrand P.P., Kunze W.A.A., Furness J.B., Bornstein J.C. (2000) The terminals of myenteric intrinsic primary afferent neurons of the Guinea-Pig ileum are excited by 5Hydroxytryptamine acting at 5Hydroxytryptamine-3 Receptors. Neuroscience. 101, 459-69. Camacho A., Dimsdale J.E. (2000) Platelets and Psychiatry: Lessons Learned from Old and New studies. Psychosom. Med. 62: 326- 336. Chen J.J., Li Z., Pan H., Murphy D.L., Tamir H., Koepsell H., Gershon M.D., (2001) Maintenance of Serotonin in the Intestinal Mucosa and Ganglia of Mice that Lack the High-Affinity Serotonin Transporter: Abnormal Intestinal Motility and the Expression of Cation Transporters. The Journal of Neuroscience. 21, 63486361. Coates M.D., Mahoney C.R., Linden D.R., Sampson J.E., Chen J., Blaszyk H., Crowell M.D., Sharkey K.A., Gershon M.D., Mawe G.M., Moses P.L. (2004) Molecular defects in mucosal serotonin content and decreased Serotonin Reuptake Transporter in Ulcerative Colitis and Irritable Bowel Syndrome. Gastroenterology. 126, 16571664. Cocchi M., Gabrielli F., Tonello L., Pregnolato M. (2010a) The Interactome Hypothesis of Depression. NeuroQuantology. 4: 603-613. Cocchi M., Tonello L., Lercker G. (2010b) Fatty acids, membrane viscosity, serotonin and ischemic heart disease. Lipids in Health and Disease. 9:97.

www.quantumbiosystems.org

Quantum Biosystems | 2011 | Vol 3 | Issue 1 | Page 12- 18 Massimo Cocchi et al

17

Cocchi M., Tonello L., (2010c) Bio molecular considerations in Major Depression and Ischemic Cardiovascular Disease. Central Nervous System Agents in Medicinal Chemistry. 10: 97-107. Cocchi M., Tonello L., De Lucia A., Amato P. (2009a) Platelet and Brain Fatty Acids: a model for the classifcation of the animals? Part 1. International Journal of Anthropology. 24, 6976. Cocchi M. Tonello L., De Lucia A., Amato P. (2009b) Platelet and Brain Fatty Acids: a model for the classification of the animals? Part 2. International Journal of Anthropology. 24, 6976. Cocchi M., Tonello L., Tsaluchidu S., Puri B.K. (2008) The use of artificial neural networks to study fatty acids in neuropsychiatric disorders. BMC Psychiatry. 8 (Suppl 1): S3. Collins S.M., Bercik P. (2009) The relationship between intestinal microbiota and the Central Nervous System in normal gastrointestinal function and disease. Gastroenterology. 136: 2003-2014. Donati R.J., Dwivedi Y., Roberts R.C., Conley R.R., Pandey G.N., Rasenick M.M. (2008) Postmortem brain tissue of depressed suicides reveals increased Gs localization in lipid raft domains where it is less likely to activate adenylyl cyclase. J Neurosci. 28: 3042-50. Dreux C., Launay J.M. (1985) Blood platelets. Neuronal Model in Psychiatric disorders. Encephale 11: 57-64. Edwards D.J., Spiker D.G., Kupfer D.J., Foster G., Neil J.F., Abrams L. (1978) Platelet monoamine oxidase in affective disorders. Arch Gen Psychiatry. 35, 1443-6. Gaginella T.S., Galligan J.J. (1995) Serotonin and gastrointestinal function. CRC Press. Graff LA, Walker JR, Bernstein CN. (2009) Depression and Anxiety in Inflammatory Bowel Disease: A Review of Comorbidity and Management. Inflamm Bowel Dis. 15:1105-18. Hameroff S., Penrose R. (1996) Orchestrated reduction of quantum coherence in brain microtubules: a model for consciousness. In: S.R. Hameroff, A. Kaszniak and A.C. Scott (eds.) Toward a Science of Consciousness - The First Tucson Discussions and Debates. MIT Press Cambridge, UK. 507- 540. Hameroff S. (2009) The conscious pilotdendritic synchrony moves through the brain to mediate consciousness. J Biol Phys. Published online,doi: 10.1007/s10867-009- 9148-x. Heron D.S., Shinitzky M., Hershkowitz M., Samuel D. (1980) Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes Proc. Natl. Acad. Sci. 77: 12, 7463-7467.

Kim H.L., Plaisant O., Leboyer M., Gay C., Kamal L., Deviynck M.A. (1982) Reduction of platelet serotonin in major depression (endogenous depression). C R Acad Sci. III. 295, 619-622. Kim H.S. (2009) 5-Hydroxytryptamine 4 receptor agonists and colonic motility. J. Smooth Muscle Res. 45: 2529. Kroft E.B.M., de Jong E.M.G.J., Evers A.W.M. (2009). Psychological Distress in Patients with Morphea and Eosinophilic Fasciitis Arch Dermatol. 145:1017-1022. Kunze W.A., Mao Y.K., Wang B., Huizinga J.D., Ma X., Forsythe P., Bienenstock J. (2009) Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calciumdependent potassium channel opening. Journal of Cellular and Molecular Medicine. 13: 22612270. Kurina L, Goldacre M, Yeates D, Gill L. (2001) Depression and anxiety in people with inflammatory bowel disease. J Epidemiol Community Health., 55:716720. Layden BT, Saengsawang W, Donati RJ, Yang S, Mulhearn DC, Johnson ME, Rasenick MM. (2008) Structural model of a complex between the heterotrimeric G protein, Gsalpha, and tubulin. Biochim Biophys Acta., 1783: 964-73. Marangos P.J. (1979) Blood Platelets Contain a Neuron-Specific Enolase Subunit. Journal of Neurochemistry. 34, 1254- 1258. Maurer-Spurej E, Pittendreigh C, Misri S. (2007) Platelet serotonin levels support depression scores for women with postpartum depression. J Psychiatry Neurosci. 32(1):23-9. Michel K., Zeller F., Langer R., Nekarda H., Kruger D., Dover T.J., Brady C.A., Barnes Michael N.M. (2005) Serotonin Excites Neurons in the Human Submucous Plexus via 5-HT3 Receptors. Gastroenterology. 128, 1317-1326. Ostojic P., Zivojinovic S., Reza T., Milivojevic D., Damjanov N. (2007). Symptoms Of Depression And Anxiety In Patients With Systemic Sclerosis: Impact Of Disease Severity And Socioeconomic Factors. THU0301. EULAR. Penrose R. and Hameroff S. (2011) Consciousness in the Universe: Neuroscience, Quantum SpaceTime Geometry and Orch OR Theory. Journal of Cosmology, Vol. 14. Plein H., Berk M. (2001) The platelet as a peripheral marker in psychiatric illness. Clin. Exp. Pharmacol., 16: 229-236. Popova J.S., Greene A.K., Wang J., Rasenick M.M. (2002) Phosphatidylinositol 4, 5-bisphosphate modifies tubulin participation in phospholipase C1 signaling. J Neurosci. 222: 1668-1678. Rotman A. (1983) Blood platelets in psychopharmacological research. Prog Neuropsychopharmacol Biol Psychiatry. 7, 3551.

ISSN 1970-223X

www.quantumbiosystems.org

Quantum Biosystems | 2011 | Vol 3 | Issue 1 | Page 12- 18 Massimo Cocchi et al

18

Samuel D. (1985) Membrane engineering to rejuvenate the ageing brain. Can Med Assoc J. 132, 325-327. Sikander A., Rana S.V., Prasad K.K. (2009) Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clinica Chimica Acta. 403, 47-55. Simon C., Ternaux J.P. (1990) Regulation of Serotonin Release from Enterochromaffin Cells of Rat Cecum Mucosa. The Journal of Pharmacology and Experimental Therapeutics. 253, 825-832. Takahashi S. (1976) Reduction of blood platelet serotonin levels in manic and depressed patients. Folia Psychiat. Neu. J. 30, 475- 486. Tonello L., Cocchi M. (2010) The Cell Membrane: Is it a Bridge from Psychiatry to Quantum Consciousness? NeuroQuantology. 8: 1, 54-60. Wang N., Rasenick M.M. (1991) Tubulin-G protein interactions involve microtubule polymerization domains. Biochemistry. 30: 10957-65. Wirz-Justice A. (1988) Platelet research in psychiatry. Experientia. 44(2): 145-52. Woolf N.J., Craddock T., Friesen D., Tuszynski J. (2010) Neuropsychiatric illness: a case for impaired neuroplasticity and possible quantum processing derailment in microtubules. NeuroQuantology. 8(1): 13-28.

ISSN 1970-223X

www.quantumbiosystems.org