EFFECTS OF THE LITHIUM – CONTAINING SORBENT ON TERMS OF BEHAVIORAL REACTIONS UNDER CHRONIC ALCOHOL INTOXICATION MODEL

Lithium preparations are widely used for stabilize mood in case of bipolar affective disorder. Currently neuroprotective and neuroregenerative effects of lithium are of interest as in case of acute brain injury, also in chronic neurodegenerative diseases such as dementia, alcoholism, Alzheimer disease, etc. [1–5]. In clinical practice use of lithium preparations is limited due to difficult adjustment of drug dosage, necessity of monitoring its concentration in blood, side effects development as a result of accumulation of lithium in a body. For the purpose of improvement of pharmacologic properties lithium is combined with other agents (for example modifying sorbent) thus it can produce longer-term and more harmless (less side reactions) effect in the long view. Lithium immobilization on sorption basis will allow to use sorbent as detoxicant and carrying agent of drugs to body.

The purpose of the work is studying the effect of the lithium – containing sorbent on terms of behavioral reactions under chronic alcohol intoxication model.

Materials and methods. During the work we used nonlinear mice – males, which weight 25–30 g (180 animals). Chronic alcohol intoxication was precipitated via 40% proof spirit injections (oral supplementation in quantity of 3 g/kg during 2 weeks), additionally mice drunk 5% proof spirit from drinking bowl. Each experimental group consisted of 10 animals. Study drugs were inserted inside while ethanol injecting. Control animals were inserted 0,9% salin solution. Emotional state of animals was assessed through forced swim test, short – term memory assessment was performed through conditioned passive avoidance reflex. Effect of chronic alcohol intoxication on the parameters of conditioned reflex activity was measured every 7 days.

Results. It was found that the investigated lithium-containing sorbent increases: the number of mice are trained passive avoidance reflex, remembering percent of electric shock animals compared to the negative control , and – the duration of the latent time of immobility in comparison with the negative control.

Conclusion. The proposed formulation of lithium (immobilized on a sorbent ) has a complex neurotropic action, showing antitoxic properties against a background of long-term administration of ethanol.

1. Chuang D.M. Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? // Crit. Rev. in Neurobiol. 2004. V. 16. R. 83-90. https://doi.org/10.1615/CritRevNeurobiol.v16. i12.90.

2. Chi-Tso Chiu, De-Maw Chuang. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders // Pharmacol. Ther. 2010. Nov. V. 128, № 2. R. 281-304. https://doi.org/10.1016/j. pharmthera.2010.07.006.

3. Wei H., Qin Z. H., Senatorov V.V., Wei W., Wang Y., Qian Y., Chuang D.M. Lithium suppresses excitotoxicity- induced striatal lesions in a rat model of Huntington’s disease // Neuroscience. 2001. Sept. V. 106, № 3. R. 603-612.

4. Noble W., Planel E., Zehr C., Olm V., Meyerson J., Suleman F., Gaynor K., Wang L., LaFrancois J., Feinstein B., Burns M., Krishnamurthy P., Wen Y., Bhat R., Lewis J., Dickson D., Duff K. Inhibition of glycogen synthase kinase- 3 by lithium correlates with reduced tauopathy and degeneration in vivo // Proc. Natl. Acad. Sci. USA. 2005. May. V. 102, № 19. R. 6990-6995. https://doi.org/10.1073/ pnas.0500466102.

5. Chuang D. M., Chen R. W., Chalecka-Franaszek E., Ren M., Hashimoto R., Senatorov V., Kanai H., Hough C., Hiroi T., Leeds P. Neuroprotective effects of lithium in cultured cells and animal models of diseases // Bipolar. Disord. 2002. Apr. V. 4, № 2. R. 129-136. https://doi.org/10.1034/j.1399-5618.2002.01179.x.

6. Chandler L.J., Sutton G. Acute ethanol inhibits extracellular signal-regulated kinase, protein kinase B, and adenosine 3’:5’-cyclic monophosphate response element binding protein activity in an age- and brain region-specific manner // Alcohol. Clin. Exp. Res. 2005. Apr. V. 29, № 4. R. 672-680. https://doi.org/10.1097/01.ALC.0000158935.53360.5F

7. Einat H., Yuan P., Gould T. D., Li J., Du J., Zhang L., Manji H. K., Chen G. The role of the extracellular signal- regulated kinase signaling pathway in mood modulation // J. Neurosci. 2003. Aug. V. 23, № 19. R. 7311-7316.

8. Bertola A., Mathews S., Sung Hwan Ki, Hua Wang, Bin Ga. Mouse model of chronic and binge ethanol feeding (the NIAAA model) // Nat. Protoc. 2013. Mar. V. 8, № 3. P. 627-637. https://doi.org/10.1038/nprot.2013.032. https://doi.org/10.1038/nprot.2013.032.

9. Golovenko N.Ya., Zhuk M.S., Zinkovskij V.G., Zhuk O.V., Kopanica M.V. Farmakokinetika ehtanola u myshej s razlichnoj alkogolnoj motivaciej [Pharmacokinetics of ethanol in mice with different alcohol motivation]. Byul. ehksper. biologii i mediciny - Bulletin of Experimental Biology and Medicine, 2001, V. 132, № 9, pp. 281-284. (in Russian).

10. Tabakoff B., Hoffman P.L. Animal models in alcohol research // Alcohol Res Health, 2000. V. 24, № 2. P. 77-84.

11. Habriev R.U. Rekomendacii po ehksperimentalnomu doklinicheskomu izucheniyu novyh farmakologicheskih sredstv [Recommendations on experimental (preclinical ) study of new pharmacological agents]. Moscow, Medicina Publ., 2005. 832 p. (in Russian).

12. Mashkovskij M.D. Lekarstvennye sredstva [Drugs]. Moscow, Novaya Volna Publ., 2005. 1216 p. (in Russian).

13. Mironov A.N., Bunatyan N.D. Rukovodstvo po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv. Chast pervaya [Guidance on conducting preclinical studies of drugs. Part One]. Moscow, Grif i K Publ., 2012. 944 p. (in Russian).

14. Porsolt R.D, Le Pichon M., Jalfre M. Depression: a new animal model sensitive to antidepressant treatments // Nature. 1977. Apr. V. 266, № 5604. P. 730-732.