Potentiation of responses to AMPA on central neurones by LY392098 and LY404187 in vivo

Enhancement of AMPA receptor mediated synaptic excitation has the potential to aid in the treatment of several psychiatric conditions. To test such claims there is a need to develop more potent compounds than those presently available and to demonstrate that they cross the blood–brain barrier to affect responses at central AMPA receptors. We have now completed in vivo tests with two such compounds, the newly discovered biarylpropylsulfonamides, LY392098 and LY404187, on spinal and hippocampal neurones in anaesthetised rats. In the initial study on spinal neurones, LY392098 (30–1000 μg/kg i.v.) dose-dependently increased responses to iontophoretically administered AMPA but not those to NMDA. Subsequently in a more detailed follow-up study on hippocampal neurones, LY392098 (1–100 μg/kg i.v.) and LY404187 (1–100 μg/kg i.v.) enhanced in a dose-dependent manner responses to AMPA. Responses to NMDA were also enhanced but to a less extent. Such enhanced responses to NMDA, but not those to AMPA, were reduced by the NMDA antagonist, ketamine (0.5–1 mg/kg i.v.) whereas the selective AMPA antagonist, LY300168 (GYKI53655; 1 mg/kg i.v.), reduced responses to both NMDA and AMPA. LY392098 also potentiated the synaptic excitation of dentate granule cells following perforant path stimulation. These combined data show that, at doses not dissimilar to those affecting behavioural responses (1–1000 μg/kg; see accompanying papers), the two new drugs cross the blood–brain barrier to affect directly the sensitivity of central AMPA receptors and enhance synaptic excitation in vivo.