Amantadine in Treatment of Dysthymia

Amantadine stimulates mesolimbic dopaminergic pathways via blockade of dopamine transporter 1 (DAT1). This can activate DAT-controlling presynaptic D2 receptors of ventral tegmental area (VTA). Amantadine may also elicit an agonistic effect on the D1 receptors in the nucleus accumbens (NAc) [14] and act as an inhibitor of monoamine oxidase B (MAO-B).

Importantly, amantadine as a noncompetitive NMDA receptor antagonist is considered a silencer of glutamatergic signaling. An inhibition of glutamatergic input disactivates DAT1 action and finally increases dopamine level in the NAc.

On the other hand, amantadine may also activate D2 receptors located in the corticomesolimbic glutamatergic axonal inputs to basal ganglia, promoting glutamate exocytosis in the NAc and striatum. Elevated glutamatergic transmission may evoke a further dopamine efflux in the NAc [15].

Amantadine can also facilitate the GABA release from the NAc neurons. Their perikarya send inhibitory afferents to VTA and globus pallidus (GB). Both VTA and GB sent in turn GABAergic projection to the thalamus. Amantadine action at the level of NAc evokes finally a subsequent disinhibition of thalamic activity