Vol. 3, No. 6, p. 257-262 - Dec. 31, 2016
Sedative-like effect of intraperitoneal GABA administration in the open field test
Augusto Pascual Ítalo Gargiulo , Santiago Marquez Herrero , Esteban Romanowicz , Manuel Alejandro Guevara , Adriana Inés Landa , José Vicente Lafuente , Humberto Luis Mesones and Pascual Ángel Gargiulo
Abstract
Gamma-Amino Butyric Acid (GABA) is the main inhibitor neurotransmitter of the Central Nervous System (CNS). Its peripheral administration has been matter of discussion. On the one hand, it has been reported that it does not cross the Blood-Brain Barrier (BBB), and, on the other hand, it has been associated with multiple therapeutic regimens and supplements by peripheral administration. The aim of the present study is to elucidate the possibility of a central sedative effect when administered peripherally. An experimental cohort of 90-day-old Holtzman male rats weighing 240-270 g was used. It was divided into 2 groups: saline-controls (n = 9) and GABA treated rats (12.5 mg/kg, n = 9). Both groups were intraperitoneally injected. The motor behavioral patterns displayed in the Opto Varimex (OVM) were studied. Vertical, horizontal, ambulatory and non-ambulatory movements and the number of movements were recorded in an automated way. Horizontal movements constitute the integration of ambulatory and non-ambulatory movements. Student t test was used comparing groups. In this experiment, there were non-significant downward trends in vertical, ambulatory, non-ambulatory and number of movements. Ambulatory and non-ambulatory tendencies acquired significance when treated together as horizontal movements (p < 0.05). We may conclude that peripheral administration of GABA produced a decrease of the horizontal movements in the open field test. It may be interpreted as a sedative effect, suggesting a passage of GABA through BBB, with central effects. However, there are several alternative possibilities to explain present findings. Other experiments will elucidate the implications or scope of the present findings.
Keywords
Gamma-amino-butiric acid (GABA); Sedation; Blood brain barrier (BBB); Rat; Behavior.
DOI
10.21472/bjbs.030602
Full text
PDF
References
Al-Sarraf, H. Transport of 14C-gamma-aminobutyric acid into brain, cerebrospinal fluid and choroid plexus in
neonatal and adult rats. Brain. Res. Dev. Brain Res., v. 139, no. 2, p. 121-129, 2002.
Baxter, C. F.; Roberts, E. The gamma-aminobutyric acid-alpha-ketoglutaric acid transaminase of beef brain.
J. Biol. Chem., v. 233, no. 5, p. 1135-1139, 1958.
Blackshaw, L. A. Receptors and transmission in the brain-gut axis: potential for novel therapies. IV.
GABA(B) receptors in the brain-gastroesophageal axis. Am. J. Physiol. Gastrointest. Liver Physiol.,
v. 281, no. 2, p. G311-G315, 2001.
Boonstra, E.; de Kleijn, R.; Colzato, L. S.; Alkemade, A.; Forstmann, B. U.; Nieuwenhuis, S. Neurotransmitters
as food supplements: the effects of GABA on brain and behavior. Front. Psychol., v. 6, p. 1520, 2015.
Dinan, T. G.; Stanton, C.; Cryan, J. F. Psychobiotics: a novel class of psychotropic. Biol. Psychiatry,
v. 74, no. 10, p. 720-726, 2013.
Elliot, K. A.; Van Gelder, N. M. Occlusion and metabolism of gamma-aminobutyric acid by brain tissue. J.
Neurochem., v. 3, no. 1, p. 28 40, 1958.
Feng, M. R.; Turluck, D.; Burleigh, J.; Lister, R.; Fan, C.; Middlebrook, A.; Taylor, C.; Su, T. Brain
microdialysis and PK/PD correlation of pregabalin in rats. Eur. J. Drug Metab. Pharmacokinet.,
v. 26, no. 1-2, p. 123-128, 2001.
Frey, H. H.; Löscher, W. Cetyl GABA: effect on convulsant thresholds in mice and acute toxicity.
Neuropharmacology, v. 9, no. 2, p. 217-220, 1980.
Gargiulo, P. A.; Viana, M. B.; Graeff, F. G.; Silva, M. A.; Tomaz, C. Effects of anxiety and memory of
systemic and intra-amygdala injection of 5-HT3 receptor antagonist BRL 46470A. Neuropsychobiology,
v. 33, no. 4, p. 189-195, 1996.
Halson, S. L. Sleep in elite athletes and nutritional interventions to enhance sleep. Sports Med.,
v. 44, Suppl. 1, p. S13-S23, 2014.
Jones, E. A.; Schafer, D. F.; Ferenci, P.; Pappas, S. C. The GABA hypothesis of the pathogenesis of hepatic
encephalopathy: current status. Yale J. Biol. Med., v. 57, no. 3, p. 301-316, 1984.
Knudsen, G. M.; Poulsen, H. E.; Paulson, O. B. Blood-brain barrier permeability in galactosamine-induced
hepatic encephalopathy. No evidence for increased GABA-transport. J. Hepatol., v. 6, no. 2,
p. 187-192, 1988.
Kuriyama, K.; Sze, P.Y. Blood-brain barrier to H3-gamma-aminobutyric acid in normal and amino oxyacetic
acid-treated animals. Neuropharmacology, v. 10, no. 1, p. 103-108, 1971.
Llano López, L. H.; Caif, F.; Fraile, M.; Tinnirello, B.; Gargiulo, A. I.; Lafuente, J. V.;
Baiardi, G. C.; Gargiulo P. A. Differential behavioral profile induced by the injection of dipotassium
chlorazepate within brain areas that project to the nucleus accumbens septi. Pharmacol. Rep.,
v. 65, no. 3, p. 566-578, 2013.
Llano López, L. H.; Caif, F.; García, S.; Fraile, M.; Landa, A. I.; Baiardi, G.; Lafuente, J. V.;
Braszko, J. J.; Bregonzio, C.; Gargiulo, P. A. Anxiolytic-like effect of losartan injected into amygdala of the
acutely stressed rats. Pharmacol. Rep., v. 64, no. 1, p. 54-63, 2012.
Löscher, W. Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and
synaptosomal fractions. J. Neurochem., v. 36, no. 4, p. 1521-1527, 1981.
Löscher, W.; Frey, H. H. Transport of GABA at the blood-CSF interface. J. Neurochem., v. 38,
no. 4, p. 1072-1079, 1982.
Maj, J.; Przewlocka, B.; Kukulka, L. Sedative action of low doses of dopaminergic agents. Pol. J. Pharmacol.
Pharm., v. 29, no. 1, p. 11 21, 1977.
Marinzalda, M. L.; Pérez, P. A.; Gargiulo, P. A.; Casarsa, B.S.; Bregonzio, C.; Baiardi, G.
Fear-potentiated behaviour is modulated by central amygdala angiotensin II AT1 receptors stimulation.
Biomed. Res. Int., v. 2014, Article ID 183248, 7 p., 2014. http://dx.doi.org/10.1155/2014/183248
Martínez, G.; Ropero, C.; Funes, A.; Flores, E.; Blotta, C.; Landa, A. I.; Gargiulo, P. A. Effects of
selective NMDA and non-NMDA blockade in the nucleus accumbens on the plus-maze test. Physiol. Behav.,
v. 76, no. 2, p. 219-224, 2002a.
Martínez, G.; Ropero, C.; Funes, A.; Flores, E.; Landa, A. I.; Gargiulo, P. A. AP-7 into the nucleus
accumbens disrupts acquisition but does not affect consolidation in a passive avoidance task. Physiol.
Behav., v. 76, no. 2, p. 205-212, 2002b.
Mayer, E. A.; Tillisch, K.; Gupta, A. Gut/brain axis and the microbiota. J. Clin. Invest., v. 125,
no. 3, p. 926-938, 2015.
Mesones, H. L.; Cia, F. M. Correlation between clinical and laboratory data in depression. Therapeutic
orientation by means of vitamins and amino acids. Acta Psiquiatr. Psicol. Am. Lat., v. 31, no. 1,
p. 25-36, 1985.
Morita, S.; Miyata S. Different vascular permeability between the sensory and secretory circumventricular
organs of adult mouse brain. Cell Tissue Res., v. 349, no. 2, p. 589-603, 2012.
Morris, G. L. Gabapentin. Epilepsia, v. 40, Suppl. 5, p. S63-S70, 1999.
Patterson, E.; Cryan, J. F.; Fitzgerald, G. F.; Ross, R. P.; Dinan, T. G.; Stanton, C. Gut microbiota, the
pharmabiotics they produce and host health. Proc. Nutr. Soc., v. 73. no. 4, p. 477-489, 2014.
Roberts, E.; Lowe, I. P.; Guth, L.; Jelinek, B. Distribution of γ-aminobutyric acid and other aminoacids
in nervous tissue of various species. J. Exp. Zool., v. 138, p. 313-328, 1958.
Roberts, E.; Kuriyama, K. Biochemical-physiological correlations in studies of the gamma-aminobutyric acid system.
Brain Res., v. 8, no. 1, p. 1-35, 1968.
Rodríguez, E. M.; Blázquez, J. L.; Guerra, M. The design of barriers in the hypothalamus allows
the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and
the latter to the cerebrospinal fluid. Peptides, v. 31, no. 4, p. 757-776, 2010.
Sapru, H. N. Role of the hypothalamic arcuate nucleus in cardiovascular regulation. Auton. Neurosci.,
v. 175, no. 1/2, p. 38-50, 2013.
Scott, L. V.; Clarke, G.; Dinan, T. G. The brain-gut axis: a target for treating stress-related disorders.
Mod. Trends Pharmacopsychiatry, v. 28, p. 90-99, 2013. http://dx.doi.org/10.1159/000343971
Shyamaladevi, N.; Jayakumar, A. R.; Sujatha, R.; Paul, V.; Subramanian, E. H. Evidence that nitric oxide
production increases gamma-amino butyric acid permeability of blood-brain barrier. Brain Res. Bull.,
v. 57, no. 2, p. 231-236, 2002.
Van Gelder, N. M.; Elliot, K. A. Disposition of gamma-aminobutyric acid administered to mammals. J. Neurochem.,
v. 3, no. 2, p. 139-43, 1958.
Waagepetersen, H. S.; Sonnewald, U.; Schousboe, A. The GABA paradox: multiple roles as metabolite,
neurotransmitter, and neurodifferentiative agent. J. Neurochem., v. 73, no. 4, p. 1335-1342, 1999.
Wall, R.; Cryan, J. F.; Ross, R. P.; Fitzgerald, G. F.; Dinan, T. G.; Stanton, C. Bacterial neuroactive
compounds produced by psychobiotics. In: Lyte, M.; Cryan, J. F. (Eds.). Microbial Endocrinology: the
microbiota-gut-brain axis in health and disease. New York: Springer, 2014. p. 221-239. (Advances in Experimental
Medicine and Biology: Microbial Endocrinology, v. 817). http://dx.doi.org/10.1007/978-1-4939-0897-4_10