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 cl aims there is a need to develop more potent compounds than those presently available and to demonstrate that they cross the blood-brain barrier to aff ect responses at central AMPA receptors. We have now completed in vivo test s with two such compounds, the newly discovered biarylpropylsulfonamides, L Y392098 and LY404187, on spinal and hippocampal neurones in anaesthetised r ats. In the initial study on spinal neurones, LY392098 (30-1000 mug/kg i.v. ) dose-dependently increased responses to iontophoretically administered AM PA but not those to NMDA. Subsequently in a more detailed follow-up study o n hippocampal neurones, LY392098 (1-100 mug/kg i.v.) and LY404187 (1-100 mu g/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 t o NMDA, but not those to AMPA, were reduced by the NMDA antagonist, ketamin e (0.5-1 mg/kg i.v.) whereas the selective AMPA antagonist, LY300168 (GYKI5 3655; 1 mg/kg i.v.), reduced responses to both NMDA and AMPA. LY392098 also potentiated the synaptic excitation of dentate granule cells following per forant path stimulation, These combined data show that, at doses not dissim ilar to those affecting behavioural responses (1-1000 mug/kg; see accompany ing papers), the two new drugs cross the blood-brain barrier to affect dire ctly the sensitivity of central AMPA receptors and enhance synaptic excitat ion in vivo. (C) 2001 Elsevier Science Ltd. All rights reserved.