Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

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Abstract

It has been shown in electrophysiological studies that the ligand L-655,708 possesses a binding selectivity and a moderate inverse agonist functional selectivity for α5-containing GABA-A receptors. The present study is aimed to investigate the antidepressant effects of the ligand L-655,708 in the forced swim test (FST) and its impact on locomotor activity in rats. The behavior of the animals was recorded with a digital camera, and the data were analyzed by one-way ANOVA, followed by Dunnett’s test. In FST, L-655,708 significantly decreased immobility time at a dose of 3 mg/kg after a single and repeated administration (p<0.05), exerting acute and chronic antidepressant effects. However, it did not induce significant differences in the time of struggling behavior during FST. Furthermore, L-655,708 did not show a significant effect on locomotor activity (p>0.05). These data suggest that negative modulation at GABA-A receptors containing the α5 subunit may produce antidepressant effects in rats. These effects were not confounded by locomotor influences.

References

  • 1. Olsen RW, Sieghart W: International Union of Pharmacology. LXX. Subtypes of gammaaminobutyric acid (A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 2008, 60:243-260.

  • 2. Korpi ER, Grunder G, Luddens H: Drug interactions at GABA(A) receptors. Prog Neurobiol 2002, 67:113-159.

  • 3. Chebib M, Johnston GA: GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology. J Med Chem 2000, 43:1427-1447.

  • 4. Chapouthier G, Venault P: GABA-A receptor complex and memory processes. Curr Top Med Chem 2002, 2:841-851.

  • 5. Krazem A, Borde N, Béracochéa D: Effects of diazepam and beta-CCM on working memory in mice: relationships with emotional reactivity. Pharmacol Biochem Behav 2001, 68:235-244.

  • 6. Rudolph U, Möhler H: Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol 2004, 44:475-98.

  • 7. Sieghart W, Ernst M: Heterogeneity of GABAA receptors: reviwed interest in the development of subtype-selective drugs. Curr Med Chem Cent Nerv Syst Agents 2005, 5:217-242.

  • 8. Izquierdo I, Medina JH: Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Mem 1997, 68:285-316.

  • 9. Pirker P, Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G: GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain, Neuroscience 2000, 101:815-850.

  • 10. Sieghart W, Sperk G: Subunit composition, distribution and function of GABAA receptor subtypes. Curr Top Med Chem 2002, 2:795-816.

  • 11. Atack JR, Pike A, Clarke A, Cook SM, Sohal B, McKernan RM, Dawson GR: Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABAA alpha5-selective compound L-655,708. Drug Metab Dispos 2006, 34:887-893.

  • 12. Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR, Hobbs SC, Marshall G, Maubach KA, Pillai GV, Reeve AJ, MacLeod AM: Identifi cation of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition. J Med Chem 2003, 46:2227-2240.

  • 13. Collinson N, Atack JR, Laughton P, Dawson GR, Stephens DN: An inverse agonist selective for alpha5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze. Psychopharmacology 2006, 188:619-628.

  • 14. Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR: An inverse agonist selective for alpha5 subunitcontaining GABAA receptors enhances cognition. J Pharmacol Exp Ther 2006, 316:1335-1345.

  • 15. Redrobe JP, Elster L, Frederiksen K, Bundgaard C, de Jong IE, Smith GP, Bruun AT, Larsen PH, Didriksen M: Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive defi cits in rats. Psychopharmacology 2012, 221:451-468.

  • 16. Porsolt RD, Anton G, Blavet N, Jalfre M: Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978, 47:379-391.

  • 17. Hines RM, Davies PA, Moss SJ, Maguire J: Functional regulation of GABA(A) receptors in nervous system pathologies. Curr Opin Neurobiol 2012, 22:552-558.

  • 18. Kalueff AV, Nutt DJ: Role of GABA in anxiety and depression. Depress Anxiety 2007, 24:495-517.

  • 19. Luscher B, Fuchs T, Kilpatrick CL: GABAA receptor traffi cking-mediated plasticity of inhibitory synapses. Neuron 2011, 70:385-409.

  • 20. Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, Mohler H, Lüscher B: GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci 2007, 27:3845-3854.

  • 21. Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, Luscher B: Gamma-Aminobutyric acid-type A receptor defi cits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry 2010, 68:512-520.

  • 22. Xing B, Zhao Y, Zhang H, Dang Y, Chen T, Huang J, Luo Q: Microinjection of valproic acid into the ventrolateral orbital cortex exerts an antidepressant-like effect in the rat forced swim test. Brain Res Bull 2011, 85:153-157.

  • 23. Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Blüthmann H, Möhler H, Rudolph U: Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci USA 2002, 99:8980-8985.

  • 24. Yee BK, Hauser J, Dolgov VV, Keist R, Möhler H, Rudolph U, Feldon J: GABA receptors containing the alpha5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear. Eur J Neurosci 2004, 20:1928-1936.

  • 25. Braudeau J, Delatour B, Duchon A, Pereira PL, Dauphinot L, de Chaumont F, Olivo- Marin JC, Dodd RH, Hérault Y, Potier MC: Specifi c targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive defi cits in Down syndrome mice. J Psychopharmacol 2011, 25:1030-1042.

  • 26. Elizalde N, Gil-Bea FJ, Ramírez MJ, Aisa B, Lasheras B, Del Rio J, Tordera RM: Longlasting behavioral effects and recognition memory defi cit induced by chronic mild stress in mice: Effect of antidepressant treatment. Psychopharmacology (Berl) 2008, 199:1-14.

  • 27. Bondi CO, Jett JD, Morilak DA: Benefi cial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 2010, 34:913-923.

  • 28. Samardžić J, Štrac DŠ, Obradović M, Oprić D, Obradović DI: DMCM, a benzodiazepine site inverse agonist, improves active avoidance and motivation in the rat, Behav Brain Res 2012, 235:195-199.

  • 29. Vollenweider I, Smith KS, Keist R, Rudolph U: Antidepressant-like properties of α2- containing GABAA receptors. Behav Brain Res 2011, 217:77-80.

  • 30. Löw K, Crestani F, Keist R, Benke D, Brünig I, Benson JA, Fritschy JM, Rülicke T, Bluethmann H, Möhler H, Rudolph U: Molecular and neuronal substrate for the selective attenuation of anxiety. Science 2000, 290:131-134.

  • 31. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM: NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011, 475:91-95.

  • 32. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000, 47:351-354.

  • 33. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS: mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010, 329:959-964.

  • 34. Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G, Epperson CN, Goddard A, Mason GF: Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 2002, 7:S71-S80.

Acta Veterinaria

The Journal of University of Belgrade

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CiteScore 2016: 0.65

SCImago Journal Rank (SJR) 2016: 0.388
Source Normalized Impact per Paper (SNIP) 2016: 0.605

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