Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP

Aniracetam, a cognition enhancer, has been recently found to preferentially increase extracellular levels of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex (PFC), basolateral amygdala and dorsal hippocampus of the mesocorticolimbic system in stroke-prone spontaneously hypertensive rats. In the present study, we aimed to identify actually active substances among aniracetam and its major metabolites and to clarify the mode of action in DA and 5-HT release in the PFC. Local perfusion of mecamylamine, a nicotinic acetylcholine (nACh) and N-methyl-D-aspartate (NMDA) receptor antagonist, into the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) completely blocked DA and 5-HT release, respectively, in the PFC elicited by orally administered aniracetam. The effects of aniracetam were mimicked by local perfusion of N-anisoyl-gamma-aminobutyric acid [corrected] (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN. The cortical DA release induced by N-anisoyl-GABA applied to the VTA was also completely abolished by co-perfusion of mecamylamine. Additionally, when p-anisic acid, another metabolite of aniracetam, and N-anisoyl-GABA were locally perfused into the PFC, they induced DA and 5-HT release in the same region, respectively. These results indicate that aniracetam enhances DA and 5-HT release by mainly mediating the action of N-anisoyl-GABA that targets not only somatodendritic nACh and NMDA receptors but also presynaptic nACh receptors.