Agmatine may act as a neurotransmitter or neuromodulator. Behaviorally, agmatine exerts antidepressant-like effects. The enzyme agmatinase degrades and thereby inactivates agmatine. The gene coding for human agmatinase is located on chromosome 1p36, a gene locus which has been linked to bipolar disorder and major depression. However, the enzyme has not yet been studied in detail in the context of neuropsychiatric diseases. We analyzed agmatinase protein expression in postmortem hippocampi of individuals with affective disorders. Agmatinase protein was detected in a subset of interneurons in the hippocampus and other brain regions. In depressive patients the number and the numerical density of agmatinase-immunopositive cell bodies was strongly elevated in all regions under study (i.e. hippocampus, habenula, insular cortex and temporal cortex). Agmatine is naturally produced by the breakdown of arginine. The cellular uptake of L-arginine and other cationic amino acids (such as L-lysine and L-ornithine) is mainly mediated by cationic amino acid transporter (CAT) proteins. In patients with mood disorder there was a circumscribed decrease in the numerical density of hCAT1 immunoreactive neurons in the CA2 region of the hippocampus.

Polyamines, including spermidine, spermine, and agmatine, serve several brain-specific functions. Polyamine transport mechanisms may account for the redistribution of these organic cations, which may also be synaptically released as neuromodulators or neurotransmitters, in the brain. Therefore, the localization of polyamine pathway enzymes, in addition to the localization and functional investigation of the polyamines itself, provides valuable insights regarding the identification of cell- and region-specific roles for polyamines, notably in the context of mental disorders and neurodegenerative diseases. Identified neuronal circuits are subject to physiological and pharmacological investigations. With this respect, we electrophysiologically studied the cerebellar cortex and the medial habenula, showing a prominent synaptic expression of spermidine synthase and agmatinase, respectively. In both areas, the relevant polyamines clearly influence the electrical activity. The medial habenula may be involved with the aetiology of major depressive disorder. In this context, the expression of agmatinase in other brain areas, e.g. the paraventricular thalamic nucleus, possibly also involved with depression, is discussed.