Inhibitors of cAMP-dependent protein kinase impair long-term memory formation in day-old chicks

There is substantial evidence that protein kinases, through the phosphorylation of substrate proteins, play a significant role in information processing in the brain, including processes underlying memory formation. Inhibition of the activity of the cyclic-adenosine monophosphate-dependent protein kinase A by the highly specific inhibitor, halofantrine, resulted in impairment of memory formation in day-old chicks trained on a single-trial passive avoidance task. A dose of 9.6 ng/chick halofantrine induced amnesia at the beginning of a protein synthesis-dependent long-term memory stage, the last of three stages of memory postulated to underly memory formation in the chick following passive avoidance learning. The concentration of halofantrine required for 50% inhibition of chick brain protein kinase A was found to be similar to that observed for bovine heart and rat liver. The amnestic effect of halofantrine is tentatively attributed to interference with de novo protein synthesis necessary for long-term memory consolidation. Neither anthraquinone nor the anthraquinone derivative anthraflavic acid, which have little effect on protein kinase A activity, affected memory retention. On the other hand, two other anthraquinone derivatives, chrysophanic acid and purpurin, which inhibit PKA activity, at doses of 0.25 and 0.5 ng/chick also yielded retention deficits. In these cases, however, retention losses occurred earlier than observed with halofantrine, at about 30 min post-training. The earlier effects of these inhibitors may be due to the additional inhibitory action of these compounds on protein kinase C activity, which has been demonstrated in previous studies to be implicated, possibly through phosphorylation of the GAP43 phosphoprotein, in memory processing in the stage of memory immediately preceding the protein synthesis-dependent long-term stage.