LOCALIZATION OF A DEFECT IN HYPOTHALAMIC DOPAMINERGIC-NEURONS OF THE AGED BRAIN THAT RESULTS IN IMPAIRED PKA-DEPENDENT ACTIVATION OF TYROSINE-HYDROXYLASE

Using an in vitro incubation system, the role of the cyclic AMP-depend ent protein kinase A (PKA) pathway in the regulation of the in situ ac tivity of tyrosine hydroxylase (TH) was studied in the hypothalamuses of young and aged ovariectomized rats. Hypothalamic tissue was incubat ed for 60 min in medium containing 3-hydroxybenzylhydrazine dihydrochl oride, a dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, and va rious agents that modify the activity of the PKA pathway. At the end o f the incubation, the tissue was homogenized and analyzed for DOPA and TH mass. The in situ molar activity of TH was expressed as the moles of DOPA accumulating in the tissue per mole of TH per hour. Forskolin, an activator of adenylyl cyclase and the cyclic AMP agonist, (Sp)-cyc lic adenosine 3',5'-monophosphothioate, significantly (P < .01) increa sed the in situ molar activity of TH in the hypothalamic dopaminergic (DAergic) neurons of both young and aged rats. Theophylline, a phospho diesterase inhibitor, did not affect the TH molar activity in the hypo thalamuses of aged animals but did significantly (P < .001) increase i ts activity in those of young rats. When vasoactive intestinal peptide was evaluated, the TH molar activity was significantly (P < .005) inc reased in the hypothalamuses of young rats but not in those of aged ra ts. It was suggested that the deficiency of DA secretion by hypothalam ic DAergic neurons of aged rats may be the result of insufficient acti vation of PKA caused by failure of transduction of an extracellular si gnal to activate adenylyl cyclase and produce cyclic AMP.