The involvement of GABAergic system in the antidepressant-like effect of agmatine
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ORIGINAL ARTICLE
The involvement of GABAergic system in the antidepressant-like effect of agmatine Vivian Binder Neis 1 & Axel Fogaça Rosado 1 & Gislaine Olescowicz 1 & Morgana Moretti 1 & Priscila Batista Rosa 1 & Nicole Platt 1 & Ana Lúcia S. Rodrigues 1 Received: 26 November 2019 / Accepted: 13 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Considering the involvement of GABAergic system in the action of the fast-acting antidepressant ketamine, and that agmatine may exert an antidepressant-like effect through mechanisms similar to ketamine, the purpose of the present study was to evaluate the involvement of GABAA and GABAB receptors in the antidepressant-like effect of agmatine. The administration of muscimol (0.1 mg/kg, i.p., GABAA receptor agonist) or diazepam (0.05 mg/kg, p.o., GABAA receptor positive allosteric modulator) at doses that caused no effect in the tail suspension test (TST) combined with a subeffective dose of agmatine (0.0001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST. In another set of experiments, the administration of baclofen (1 mg/kg, i.p., GABAB receptor agonist) abolished the reduction of immobility time in the TST elicited by agmatine (0.1 mg/kg, p.o., active dose). In another cohort of animals, treatment with NMDA (0.1 pmol/site, i.c.v.) prevented the antidepressant-like effect of the combined administration of agmatine and muscimol as well as ketamine and muscimol in the TST. Results suggest that the effect of agmatine in the TST may involve an activation of GABAA receptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABAB receptors. Keywords Agmatine . Antidepressant . GABA . Ketamine . Tail suspension test
Introduction Major depressive disorder (MDD) is a debilitating psychiatric disorder that affects a considerable part of population around the world (Clevenger et al. 2018). Although its etiology is not completely understood, studies have demonstrated the involvement of GABAergic system in MDD. Indeed, postmortem evidence and preclinical studies have highlighted GABAergic abnormalities, such as a reduction in GABA in patients with depression (Bhagwagar et al. 2008; Price et al. 2009). In addition, the role of GABAergic system in the pathophysiology of MDD has been suggested by several studies that indicate (a) stressrelated changes in GABAergic function (Biggio et al. 1990;
* Vivian Binder Neis [email protected] 1
Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC 88040-900, Brazil
Banasr et al. 2017); (b) the ability of GABA agonists and antagonists to modulate the behavioral responses in models of depression in rodents (Song and Leonard 2005); (c) elevated GABA levels in rat thalamus following acute administration of tricyclic antidepressants (Korf and Venema 1983); (d) GABAergic abnormalities and genetic associations in depressed patients (Petty et al. 1999; Oh et al. 201
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