BRAIN SEROTONIN2 AND SEROTONIN1A RECEPTORS ARE ALTERED IN THE CONGENITALLY HYPERAMMONEMIC SPARSE FUR MOUSE

In previous studies we documented an increase in the levels of the serotonin metabolite, 5-hydroxyindoleacetic acid, in the congenitally hyperammonemic sparse fur mouse. To extend these findings, brain serotonin receptors were studied in these animals. Radioligand binding assays were performed using [H-3]ketanserin to label serotonin2 sites and 8-[H-3]hydroxy(di-n-propylamino)tetralin to label serotonin1A sites in cortical membrane homogenates. The capacity (B(max)) for [H-3]ketanserin binding was significantly lower (-21%; p < 0.05) in sparse fur animals than in control animals; there was no change in affinity (K(D)). In contrast, the capacity for 8-[H-3]hydroxy(di-n-propylamino)tetralin binding was significantly greater (26%; p < 0.05) in sparse fur compared with control animals. No difference in affinity was observed. Using two behavioral assays, the functional responsiveness of these serotonin receptors was compared in sparse fur and control animals. Head twitch activity elicited by administration of the serotonin agonist quipazine was studied as a behavior mediated by serotonin2 receptors. Compared with controls, sparse fur mice demonstrated a significantly decreased head twitch response (p < 0.005). Hypothermia elicited by administration of 8-hydroxy(di-n-propylamino)tetralin was studied as a physiologic response mediated by serotonin1A receptors. Although there were not overall group differences in the dose-response data, there was a significant increase in the hypothermia induced by 8-hydroxy(di-n-propylamino)tetralin in sparse fur compared with control mice (p < 0.02) at the highest dose. These data provide further support for a link between hyperammonemia and alterations in the serotonin system.