CHRONIC ACTIVATION OF THE CYCLIC-AMP SIGNALING PATHWAY PROMOTES DEVELOPMENT AND LONG-TERM SURVIVAL OF MESENCEPHALIC DOPAMINERGIC-NEURONS

Dibutyryl cyclic AMP (dbcAMP), a permeant analogue of cyclic AMP (cAMP ), prevented, for at least 3 weeks, the death of tyrosine hydroxylase (TH)-immunopositive dopaminergic neurons, which occurred spontaneously by apoptosis in mesencephalic cultures. Treatment with the cyclic nuc leotide analogue also led to a significant increase in the uptake of [ H-3]dopamine, attesting that the rescued TH+ neurons were fully functi onal and differentiated. dbcAMP was most effective when added immediat ely after plating, but delayed treatment could still arrest the ongoin g degenerative process. Trophic/survival effects were long-lasting, de clining only progressively after withdrawal of dbcAMP from the culture medium. They were independent of cell density and still delectable in the absence of serum proteins. The effects of dbcAMP were mimicked by depolarizing concentrations of potassium and by agents that increase endogenous production of cAMP, such as forskolin or 3-isobutyl-1-methy lxanthine, but not by native cAMP, which cannot cross cell membranes. Elimination of glial cells by arabinoside-C did not reduce the activit y of dbcAMP. GABAergic neurons, also present in these cultures, were m uch less dependent on the cyclic nucleotide analogue for their surviva l, and serotoninergic cells were not dependent at all. Therefore, cAMP -dependent signaling may be particularly crucial for the maturation an d long-term survival of mesencephalic dopaminergic neurons.