γ-Aminobutyric acid (GABA)- and serotonin (5-HT)-mediated cell signaling, neuronal survival enhancement, and reduced neuronal death in brainstem during liver injury followed by active liver regeneration have a critical role in maintaining routine bodily functions. In the present study, GABAB and 5-HT2A receptor functional regulation, interrelated actions of neuronal survival factors, and expression of apoptotic factors in the brainstem during GABA and 5-HT chitosan nanoparticles-induced active liver regeneration in partially hepatectomized rats were evaluated. Partially hepatectomized rats were treated with the nanoparticles, and receptor assays and confocal microscopic studies of GABAB and 5-HT2A receptors, gene expression studies of GABAB and 5-HT2A receptors, nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), Akt-1, phospholipase C, Bax, and caspase-8 were performed with the brainstems of experimental animals. A significant decrease in GABAB and 5-HT2A receptor numbers and gene expressions denoted a homeostatic adjustment by the brain to trigger the sympathetic innervations during elevated DNA synthesis in the liver. The neuronal apoptosis resulting from the loss of liver function after partial hepatectomy was minimized by nanoparticle treatment in rats compared with rats with no treatment during regeneration. This was confirmed from the gene expression patterns of NF-κB, TNF-α, Akt-1, phospholipase C, Bax, and caspase-8. The present study revealed the potential of GABA and 5-HT chitosan nanoparticles for increasing neuronal survival in the brainstem during liver injury following regeneration, which avoids many neuropsychiatric problems. © 2013 Wiley Periodicals, Inc.