Hippocampal levels of phosphorylated protein kinase A (phosphor-S96) are linked to spatial memory enhancement by SGS742.

Cognitive enhancement by the GABA (B) receptor antagonist SGS742 has been well-documented, but mechanisms of action are not fully elucidated. Previous work has proposed involvement of somatostatin-14 and protein kinase C in cognitive enhancement; phospho-protein kinase A (p-PKA), fyn, and phospho-fyn are known signaling systems for spatial memory. It was the aim of the study to determine hippocampal levels of these proteins following SGS742-treatment and to correlate them with the outcome from the Morris water maze (MWM), represented by the parameter "time spent in the target quadrant" during the probe trial. OF1 mice were used for the experiments and divided into four groups: intraperitoneal SGS742 and saline solution treatment, both, tested in the MWM, and two yoked controls. Six hours following the probe trial, hippocampal protein levels were determined by immunoblotting. In the MWM, time spent in the target quadrant was significantly enhanced by SGS742 treatment. p-PKA levels were significantly increased only in the SGS742-treated group tested in the MWM as compared to saline treatment. In yoked controls, no significant differences in p-PKA levels between SGS742 and saline treatment were observed. Somatostatin-14 levels were significantly increased in both SGS742-treated groups. No statistically significant changes of other protein levels were observed. We propose that GABA (B) antagonism represented by SGS742 treatment led to cognitive enhancement involving p-PKA, because yoked controls treated with SGS742 were comparable to yoked saline-treated controls. The finding that somatostatin-14 was also induced in the SGS742-treated yoked controls points to a drug side effect, and therefore the role of somatostatin-14 for cognitive enhancement remains open. Copyright 2008 Wiley-Liss, Inc.