Objectives: To study the pharmacological interactions between agmatine and gamma aminobutyric acid (GABA) modulatory agents in the regulation of anxiety-like behavior in rats.
Materials and methods: Male Wistar rats were treated drugs per se or in combination and 15 min after last injection were subjected to elevated plus-maze (EPM) test. Anxiety-like behavior was evaluated by measuring behavioral conventional readout, open arm activity (duration and/or entries) for 5-minute duration.
Results: Acute intra-central amygdala (CeA) injection of agmatine (0.1-0.6 μmol/site/rat), muscimol (0.25-1 nmol/site/rat), diazepam (5-20 μg/site/rat) and allopregnanolone (2-8 μg/site/rat) increased open arm entries of the rats in EPM suggesting anxiolytic effect in dose dependent manner. Moreover, the anxiolytic effect at subeffective dose of agmatine (0.1 μmol/site/rat) was potentiated by subeffective dose of muscimol (0.25 nmol/site/rat), diazepam (5 μg/site/rat) and allopregnanolone (4 μg/site/rat). Whereas, pretreatment with GABAA receptor antagonist, bicuculline (10 ng/site/rat) blocked the anxiolytic effect of agmatine and its synergistic effect of agmatine plus muscimol. Similarly, benzodiazepine (BZD) receptor antagonist, flumazenil (15 μg/site/rat) and GABA allosteric modulator antagonist, RO 15-45 13 (10 μg/site/rat) reduced the anxiolytic effect of agmatine, given alone and with diazepam and allopregnanolone, respectively.
Conclusion: These results indicated that anxiolytic effect of agmatine is medicated via GABAergic mechanisms, probably conciliated by the GABAA receptor subtypes. Modulation of interplay between agmatine and GABAA receptor activity might be a pertinent solution for the regulation of anxiety.
Keywords: Agmatine; anxiety; central nucleus of amygdala; elevated plus-maze; gABA.