Potential antidepressant LY 367265 presynaptically inhibits the release of glutamate in rat cerebral cortex.
Abnormality of glutamate, one of the excitatory neurotransmitters, has been implicated in psychiatric disorders such as depression. In this study, the effect of the potential antidepressant LY 367265, an inhibitor of the 5-hydroxytryptamine (5-HT) transporter and 5-HT2A receptor antagonist, on the release of endogenous glutamate was investigated in nerve terminals purified from rat cerebral cortex using an on-line enzyme-coupled fluorimetric assay. LY 367265 inhibited the release of glutamate evoked by 4-aminopyridine (4AP) in a concentration-dependent manner; no effect was seen on KCl-evoked glutamate release. Examination of the effect of LY 367265 on cytosolic [Ca(2+)] revealed that the attenuation of glutamate release could be attributed to a reduction in Ca(2+) influx. The inhibition of Ca(2+) influx by LY 367265 was most likely due to it decreasing synaptosomal excitability because LY 367265 significantly reduced the 4AP-evoked depolarization of the synaptosomal plasma membrane potential. Glutamate release induced by the Ca(2+) ionophore ionomycin was not affected by LY 367265, indicating that LY 367265-mediated inhibition of glutamate release is not a direct interference in the release process at some point subsequent to Ca(2+) influx. Together, these results suggest that LY 367265 effects a decrease in the nerve terminal excitability, which subsequent attenuates the Ca(2+) entry through voltage-dependent Ca(2+) channels to cause a decrease in evoked glutamate release. Additionally, compared with the clinically effective antidepressant fluoxetine, a selective serotonin reuptake inhibitor, LY 367265 seems to have a more potent inhibition on 4AP-evoked glutamate release. Furthermore, the finding that LY 367265 and fluoxetine responses were additive suggests that the simultaneous blockade of 5-HT(2A) receptors and 5-HT uptake transporters might have greater therapeutic efficacy than either action alone.
Wang
Su-Jane
SJ
School of Medicine, Fu Jen Catholic University, Taipei Hsien, Taiwan 24205. med0003@mails.fju.edu.tw
D015761:4-Aminopyridine / Q000037:antagonists & inhibitors; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*
D015761:4-Aminopyridine; D000928:Antidepressive Agents; D015220:Calcium Channels; D003499:Cyclic S-Oxides; D005473:Fluoxetine; D018698:Glutamic Acid; D015759:Ionomycin; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044402:Receptor, Serotonin, 5-HT2A; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013830:Thiadiazoles; C417213:LY 367265; C493232:Slc6a4 protein, rat