EFFECTS OF CHRONIC ACTIVATION OF DOPAMINE D-2 RECEPTORS IN CULTURES OF RAT FETAL DOPAMINERGIC-NEURONS - INDICATIONS FOR ALTERATIONS IN FUNCTIONAL-ACTIVITY

In Parkinsonian patients, previously subjected to neuronal grafting th erapy, the survival and functional status of dopaminergic grafts might be impaired by the concurrent pharmacotherapy with L-DOPA and/or dopa mine (DA) D-2 receptor agonists. To test this hypothesis in vitro, we studied the effects of chronic DA D-2 receptor activation on the funct ional capacity of cultured fetal rat mesencephalic DA neurons, using t he activity of tyrosine hydroxylase (TH) and the intracellular dopamin e content as neurochemical parameters. In cellular extracts prepared f rom our cultures, TH activity (as determined by the release of (H2O)-H -3 from H-3-[3,5] tyrosine) appeared to be tetrahydrobiopterin-, Fe2+, and temperature sensitive, while in intact cells, the catalytic activ ity of TH could be induced by K+-evoked depolarization in a Ca2+-depen dent way. In contrast, no acute BA D-2 receptor mediated inhibitory ef fects could be demonstrated in intact cells, either when tested under basal or depolarizing conditions. Nevertheless, after chronic exposure to DA D-2 receptor agonists for 14 days clear differences were observ ed in the functional status of cultured fetal dopaminergic neurons. Th us, whereas the overall survival and basal TH activity of cultured fet al dopaminergic neurons remained virtually unaltered, the depolarizati on induced activation of TH was enhanced in agonist-treated cultures. Moreover, after long-term treatment for 14 or 21 consecutive days, the intracellular DA content of agonist treated cultures appeared to be h igher, as compared to untreated controls. It is concluded that chronic activation of DA D-2 receptors may induce adaptive alterations in the functional activity of cultured fetal dopaminergic neurons. The possi ble consequences of these changes for the functional activity of (graf ted) fetal dopaminergic neurons are discussed.