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 therapy, the survival and functional status of dopaminergic grafts might be impaired by the concurrent pharmacotherapy with l-DOPA and/or dopamine (DA) D-2 receptor agonists. To test this hypothesis in vitro, we studied the effects of chronic DA D-2 receptor activation on the functional capacity of cultured fetal rat mesencephalic DA neurons, using the activity of tyrosine hydroxylase (TH) and the intracellular dopamine content as neurochemical parameters. In cellular extracts prepared from our cultures, TH activity (as determined by the release of 3H 2O from 3H-[3,5] tyrosine) appeared to be tetrahydrobiopterin-, Fe 2+, and temperature sensitive, while in intact cells, the catalytic activity of TH could be induced by K +-evoked depolarization in a Ca 2+-dependent way. In contrast, no acute DA D-2 receptor mediated inhibitory effects 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 observed in the functional status of cultured fetal dopaminergic neurons. Thus, whereas the overall survival and basal TH activity of cultured fetal dopaminergic neurons remained virtually unaltered, the depolarization 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 higher, 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 possible consequences of these changes for the functional activity of (grafted) fetal dopaminergic neurons are discussed.