Fig. 1

Potential mechanism of action of agmatine against withdrawal syndrome. Agmatine may block NMDA (N-methyl-D-aspartate) receptor found on GABAergic interneurons. This leads to dis-inhibition of GABAergic interneurons and increases the firing activity in pyramidal cells that induces glutamate release. Consequently, extracellular glutamate increases and activates AMPA receptor that stimulates mTOR pathway. Agmatine may also inhibit NMDA receptor on post glutamatergic neuron. This leads to reduction in eEF2 (eukaryotic elongation factor 2) phosphorylation that de-suppresses translation of BDNF. Glutamate is transferred to GABA interneuron by EAAT3 (excitatory amino acid transporter) and to Glial neuron by EAAT1/2 transporters. GABA is produced from glutamate by the action of enzyme GAD (glutamic acid decarboxylase). Glutamate is converted in glutamine by GS (glutamine synthetase). GABA B receptor is activated by binding of GABA that causes hyperpolarization of neuron hence limiting release of glutamate. Extracellular levels of glutamate are reduced by glial cells by transforming into glutamine. Glutamine is stocked until necessary and transported into presynaptic neuron by glutamine transporter. Glutamate is then stocked into presynaptic neuron by VGluT (vesicular glutamate transporters). Agmatine may also bind to GABA A receptor that leads to the hyperpolarization of receptor