PERIPHERAL BENZODIAZEPINE STIMULATES SECRETION OF GROWTH-HORMONE AND MITOCHONDRIAL PROLIFERATION IN PITUITARY-TUMOR GH(3) CELLS

High affinity receptors for peripheral benzodiazepines (PBD) are prese nt within the pituitary gland. Wether these receptors influence cell g rowth, mitochondrial morphology and secretion of growth hormone was ex amined in pituitary tumour GH(3) cells. Cells were incubated in medium with either 10% calf serum, or serum free medium, or serum free mediu m plus 10 nM of selective PBD ligands (PK11195 or Ro5-4846) or a centr al benzodiazepine ligand (clonazepam). Peripheral or central ligands h ad no effect on cell growth. Quantitative electron micrography, howeve r, revealed that cells treated with PBDs had a 2.5-fold increase in th e total mitochondrial area within cells, a 1.6-fold increase in the nu mber of mitochondria, and a 2.0 to 2.7-fold increase on the number of dividing mitochondria compared to serum free controls. The activity of DNA polymerase gamma, which replicates mitochondrial DNA, was increas ed approximately 3 times the initial value after 6 h exposure to PBDs. The number of nucleolar organizer regions (NORs), which relate to the ultimate synthesis of cellular protein, showed a 1.4-fold increase in PBDs treated cells. Secretion of growth hormone was stimulated (240% of serum free control) by exposure to PBDs for 12 h. The central benzo diazepine ligand, clonazepam, had little effect on mitochondrial morph ology or secretion of growth hormone. These findings suggest that PBD receptors may be involved in mitochondrial proliferation and may affec t the secretion of pituitary hormones.