Role of AMPA receptor desensitization and the side effects of a DMSO vehicle on reticulospinal EPSPs and locomotor activity.
Activation of the vertebrate locomotor network is mediated by glutamatergic synaptic drive, normally initiated by the brain stem. Previous investigations have studied the role of glutamate receptors, especially NMDA receptors, in generating and regulating locomotor pattern generation. Few studies, however, have focused on the role of AMPA receptors in shaping network activity, especially with regard to their rapid desensitization. It is important to determine whether AMPA receptor desensitization plays a role in regulating neuronal network activity. We examined this question on both the network and synaptic levels in the lamprey (Lampetra fluviatilis) spinal cord using a selective and potent inhibitor of AMPA receptor desensitization, cyclothiazide (CTZ). The solvent dimethyl sulfoxide (DMSO) is commonly used to dissolve this drug, as well as many others. Unexpectedly, the vehicle alone already at 0.02%, but not at 0.01%, caused significant increases in excitatory postsynaptic potential (EPSP) amplitudes and NMDA-induced locomotor frequency. The results indicate that DMSO may have a profound influence when used > or = 0.02%, a concentration 10-50 times less than that most commonly used. Subsequently we applied CTZ concentrations < or =10 microM (DMSO < or =0.01%). CTZ (1.25-5 microM) caused an appreciable and significant increase in EPSPs mediated by non-NMDA receptors and in both AMPA- and NMDA-induced locomotor frequency, but no effects on EPSPs mediated by NMDA receptors. From the effects of CTZ it is apparent that AMPA receptor desensitization plays an important role in determining locomotor frequency and that this is likely a result of its limiting function on AMPA receptor-mediated EPSPs.
Tsvyetlynska
Nataliya A
NA
Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska institutet, Stockholm, Sweden.
Hill
Russell H
RH
Grillner
Sten
S
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001581:Benzothiadiazines / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D007798:Lampreys; D009043:Motor Activity / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects; D016571:Neural Networks, Computer; D009474:Neurons / Q000502:physiology; D018091:Receptors, AMPA / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D001581:Benzothiadiazines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; C004639:cyclothiazide; D004121:Dimethyl Sulfoxide