Effect of Age on Brain Cortical Protein Kinase C and Its Mediation of 5‐Hydroxytryptamine Release

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Abstract
The effects of age on the activity and translocation of protein kinase C (PKC) and on the facilitation of 5‐hydroxytryptamine (5‐HT, serotonin) release induced by PKC activation with the phorbol ester phorbol 12‐myristate 13‐acetate were investigated. The activities of cortical PKC and its translocation in response to K+ depolarization and phorbol ester stimulation were reduced during aging in Fischer‐344 rats. Parietal cortical brain slices from 6‐, 12‐, and 24‐month‐old animals were preloaded with [3H]5‐HT and release was evoked by 65 mM K+ or the calcium ionophore A23187. 5‐HT release induced by either K+ or A23187 was found to be reduced in 12‐ and 24‐month‐old as compared to 6‐month‐old animals. This decrease was not reversed by high extracellular Ca2+. Activation of PKC resulted in a facilitated transmitter release in tissue from 6‐ and 12‐month‐old animals but reduced [3H]5‐HT release in slices from 24‐month‐old animals. These responses were prevented by the putative PKC inhibitor 1‐(5‐isoquinolinesulfonyl)‐2‐methylpiperazine (H‐7), but not by increasing extracellular or intracellular Ca2+. The results demonstrate an age‐related change (1) in brain PKC activity and translocation and (2) in a physiological response to PKC stimulation. These results may have implications for other PKC‐mediated functions that are altered during senescence.