Correlation between 5-HT sub(7) receptor affinity and protection against sound-induced seizures in DBA/2J mice

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT sub(7) receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT sub(7) receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT sub(7) receptor and a statistically significant correlation was observed between 5-HT sub(7) affinity and doses for half-maximal response (ED sub(50)) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT sub(1A), 5-HT sub(2A) or 5-HT sub(2C) receptors. It is also unlikely that interactions between the 5-ht sub(5) receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht sub(5) receptor. There are similarities between the pharmacology of the 5-HT sub(7) receptor and that of the 5-HT sub(1A) receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT sub(1A) affinity was not significant. Furthermore, the 5-HT sub(1A) receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT sub(1A) receptor-mediated effects in mice. These data suggest that antagonism of 5-HT sub(7) receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT sub(7) antagonists.