Biphasic Modulation of Absence Seizures by Lisuride in GAERS: Dissecting the Role of 5-HT2A Receptors

Serotonergic signalling modulates absence seizures, and activation of 5-HT2A receptors with TCB-2 suppresses spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). We investigated the effects of lisuride, a serotonergic and dopaminergic ligand with low 5-HT2A receptor signalling efficacy, and examined the contribution of these receptors. Spontaneous seizures were recorded in freely moving male GAERS following systemic administration of lisuride (0.1 or 0.5 mg/kg), with or without pretreatment with the 5-HT2A receptor antagonist MDL11,939. Low-dose lisuride produced a modest pro-absence effect, whereas the higher dose produced a biphasic response: early seizure suppression followed by increased seizure activity. MDL11,939 did not abolish the early suppression, but the late increase observed with lisuride alone was not observed following pretreatment. These findings suggest that the early and late responses involve different mechanisms, with 5-HT2A receptors potentially contributing to the later phase. Lisuride’s effects differ from those reported for the potent 5-HT2A receptor TCB-2, consistent with its broader receptor profile. Further work is needed to determine the contribution of its other targets, including dopaminergic receptors.