CORRELATION BETWEEN 5-HT7 RECEPTOR AFFINITY AND PROTECTION AGAINST SOUND-INDUCED SEIZURES IN DBA 2J MICE/

Audiogenic seizures can be induced in DBA/2J mice following intense au ditory stimulation. A number of neurotransmitters, including 5-hydroxy tryptamine (5-HT), an 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, receptor may protect DBA/2J mice from audio genic seizures by attempting to correlate in vivo potency of compounds with their affinity al tl-Ie 5-HT7 receptor. All compounds used in th e correlation were shown to be antagonists at the 5-HT7 receptor and a statistically significant correlation was observed between 5-HT7 affi nity and doses for half-maximal response (ED50) for protection of DBA/ 2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significa nt correlation was observed between in vivo activity and affinity at e ither 5-HT1A, 5-HT2A or 5-HT2C receptors. It is also unlikely that int eractions between the 5-ht(5) receptor will protect DBA/2J mice from a udiogenic seizures since metergoline and mesulergine which are both ac tive in this in vivo model have no affinity for the 5-ht(5) receptor T here are similarities between the pharmacology of tl-Ie 5-HT7 receptor and tfiat of the 5-HT1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT1A affinity was not significan t. Furthermore, the 5-HT1A receptor antagonist WAY 100135 did not prot ect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT 7 receptor-mediated effects in mice. These data suggest that antagonis m of 5-HT7 receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selecti ve 5-HT7 antagonists.