iem-1754 and 1-phenylcyclohexylamine

The action of non-competitive glutamate receptor antagonists on the effects of sleep deprivation has been studied on Krushinskii-Molodkina rats having an inherited predisposition to audiogenic seizures and Wistar rats deprived to this respond. Two types of glutamate receptor open channels blockers were used: the selective blockers of NMDA-receptors (memantine and IEM-1921) and blockers of mixed type, impacting both on the NMDA- and presumably Ca(2+)-permeable AMPA/kainate receptors (IEM-1754 and IEM 1925). Rats were subjected to 12 hours long sleep deprivation. Immediatly after that memantine and IEM-1921 were injected, and during the first 3 hours the total or partial reduction of fast-wave (paradoxical) sleep and a significant increase of the representation of wakefulness at the cost of reducing the total time of slow-wave sleep were observed. These effects are most likely to be a consequence of the blockade of NMDA-receptors functioning in the systems of the rat brain responsible for the launch and maintenance of fast-wave sleep. Injection of IEM-1754 and IEM-1925 on background of sleep deprivation did not affect the organization of sleep during the first 3 hours of their action. During the second three-hour period the rebound effect was observed. The obtained results indicate the involvement of NMDA glutamate receptors in the functioning of various parts of the sleep system of both rat lines.

Topics: Adamantane; Animals; Cyclohexylamines; Diamines; Electroencephalography; Injections, Intramuscular; Male; Memantine; Quaternary Ammonium Compounds; Rats; Rats, Transgenic; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Sleep Deprivation; Sleep, REM; Wakefulness

The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.

Topics: Acoustic Stimulation; Adamantane; Animals; Cyclohexylamines; Diamines; Drug Administration Schedule; Epilepsy, Reflex; Excitatory Amino Acid Antagonists; Injections, Intramuscular; Male; Memantine; Motor Activity; Quaternary Ammonium Compounds; Rats; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Seizures

The effects of non-competitive glutamate receptor antagonists on sleep-waking organization have been studied on Krushinskii-Molodkina rats having an inherited predisposition to audiogenic seizures and Wistar ones which are resistant to this action of sound. Two types of blockers of glutamate receptor open channels were used: selective blockers of NMDA receptors (memantine and IEM-1921) and blockers of mixed type, impacting both on the NMDA and Ca-permeable AMPA/ kainate receptors (IEM-1754 and IEM 1925). During the first 3 hours after administration of these glutamate antagonists the total or partial deprivation of fast-wave sleep was provoked. Additionally the selective NMDA receptor blocking drugs (memantine, IEM-1921) induced in the same period a significant increase of the representation of wakefulness at the cost of reducing of the total time of slow-wave sleep. These effects are most likely to be a consequence of the blockade of NMDA receptors responsible for the launch and maintenance of wakefulness, slow- and fast-wave sleep. In the same first 3 hours period after the administration of IEM-1754 and IEM-1925 the organization of sleep was not significantly affected. The evident reduction of wakefulness, total duration and increase of slow-wave sleep impact was observed, during the second three-hour period. It, apparently, can be caused by the blockade of AMPA/kainate receptors. The obtained results indicate the involvement of NMDA and AMPA/kainate receptors in the functioning of various parts of the sleep system of rats belonging to both lines.

Topics: Adamantane; Animals; Cyclohexylamines; Diamines; Epilepsy, Reflex; Excitatory Amino Acid Antagonists; Male; Memantine; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Sleep