ABSTRACT
In the present study, serotonin 2C (5-HT(2C)) receptor binding parameters in the brainstem and cerebral cortex were investigated during liver generation after partial hepatectomy (PH) and N-nitrosodiethylamine (NDEA) induced hepatic neoplasia in male Wistar rats. The serotonin content increased significantly (p<0.01) in the cerebral cortex after PH and in NDEA induced hepatic neoplasia. Brain stem serotonin content increased significantly (p<0.05) after PH and (p<0.001) in NDEA induced hepatic neoplasia. The number and affinity of the 5-HT(2C) receptors in the crude synaptic membrane preparations of the brain stem showed a significant (p<0.001) increase after PH and in NDEA induced hepatic neoplasia. The number and affinity of 5-HT(2C) receptors increased significantly (p<0.001) in NDEA induced hepatic neoplasia in the crude synaptic membrane preparations of the cerebral cortex. There was a significant (p<0.01) increase in plasma norepinephrine in PH and (p<0.001) in NDEA induced hepatic neoplasia, indicating sympathetic stimulation. Thus, our results suggest that during active hepatocyte proliferation 5-HT(2C) receptor in the brain stem and cerebral cortex are up-regulated which in turn induce hepatocyte proliferation mediated through sympathetic stimulation.
Subject(s)
Brain/metabolism , Cell Proliferation , Liver Neoplasms, Experimental/metabolism , Liver Regeneration , Liver/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Binding, Competitive , Brain Stem/metabolism , Carcinogens , Cerebral Cortex/metabolism , Diethylnitrosamine , Hepatocytes/metabolism , Liver/innervation , Liver Neoplasms, Experimental/chemically induced , Male , Norepinephrine/metabolism , Rats , Rats, Wistar , Serotonin/metabolism , Sympathetic Fibers, Postganglionic/metabolism , Synaptic Membranes/metabolism , Up-RegulationABSTRACT
GABAergic alterations in brain stem during compensatory hyperplasia after partial hepatectomy (PH), lead nitrate (LN)-induced direct hyperplasia, and N-nitrosodiethylamine (NDEA)-induced neoplasia in liver were investigated. GABA content decreased in brain stem of PH- and NDEA-treated rats while it increased in LN-treated rats. GABA(A) receptor number and affinity in brain stem membrane preparations of rats showed a significant decrease in PH- and NDEA-treated rats. The GABA(B) receptor number increased in PH- and NDEA-treated rats with an increase in affinity. The results of the present study indicate that liver cell proliferation is influencing the brain stem GABAergic neurotransmission and these changes regulate the hepatic proliferation through the sympathetic stimulation.
Subject(s)
Brain Stem/metabolism , Cell Division/physiology , Liver/cytology , Receptors, GABA/physiology , Animals , Baclofen/metabolism , Chromatography, High Pressure Liquid , Male , Protein Binding , Radioligand Assay , Rats , Rats, Wistar , Receptors, GABA/metabolismABSTRACT
In the present study, the involvement of GABA(B) binding parameters were analyzed in partial hepatectomized (PH), lead nitrate (LN) induced hyperplastic and N-nitrosodiethylamine (NDEA) treated neoplastic rat livers at the peak DNA synthesis. The receptor up-regulated significantly in NDEA treated group compared with respective control. The affinity of the receptor decreased in PH while it increased in LN treated rats. In the other groups, the binding parameters remained unaltered. The displacement analysis using GABA(B) receptor agonist, [3H]baclofen, against baclofen showed a shift in affinity of the receptor towards high-affinity in PH rats and towards low-affinity in LN treated rats. Baclofen dose-dependently induced EGF mediated DNA synthesis in primary hepatocyte cultures. Also, it significantly reduced the TGFbeta1 suppression of EGF induced DNA synthesis. The effect of baclofen on hepatocyte DNA synthesis was abolished by the addition of G(i)-protein inhibitor, pertussis toxin, suggesting the involvement of GABA(B) receptor mechanisms in hepatocyte DNA synthesis. Baclofen alone could not elicit any significant change in DNA synthesis. Thus, our results show that GABA(B) receptor enhancement induce hepatic neoplasia. Also, baclofen is seen to act as a potent co-mitogen, triggering DNA synthesis in primary cultures of rat hepatocytes, mediated through the G(i) protein coupled GABA(B) receptors.
