At clinically relevant concentrations the anaesthetic/amnesic thiopental but not the anticonvulsant phenobarbital interferes with hippocampal sharp wave-ripple complexes.
BACKGROUND
Many sedative agents, including anesthetics, produce explicit memory impairment by largely unknown mechanisms. Sharp-wave ripple (SPW-R) complexes are network activity thought to represent the neuronal substrate for information transfer from the hippocampal to neocortical circuits, contributing to the explicit memory consolidation. In this study we examined and compared the actions of two barbiturates with distinct amnesic actions, the general anesthetic thiopental and the anticonvulsant phenobarbital, on in vitro SPW-R activity.


RESULTS
Using an in vitro model of SPW-R activity we found that thiopental (50-200 muM) significantly and concentration-dependently reduced the incidence of SPW-R events (it increased the inter-event period by 70-430 %). At the concentration of 25 muM, which clinically produces mild sedation and explicit memory impairment, thiopental significantly reduced the quantity of ripple oscillation (it reduced the number of ripples and the duration of ripple episodes by 20 +/- 5%, n = 12, P < 0.01), and suppressed the rhythmicity of SPWs by 43 +/- 15% (n = 6, P < 0.05). The drug disrupted the synchrony of SPWs within the CA1 region at 50 muM (by 19 +/- 12%; n = 5, P < 0.05). Similar effects of thiopental were observed at higher concentrations. Thiopental did not affect the frequency of ripple oscillation at any of the concentrations tested (10-200 muM). Furthermore, the drug significantly prolonged single SPWs at concentrations >/=50 muM (it increased the half-width and the duration of SPWs by 35-90 %). Thiopental did not affect evoked excitatory synaptic potentials and its results on SPW-R complexes were also observed under blockade of NMDA receptors. Phenobarbital significantly accelerated SPWs at 50 and 100 muM whereas it reduced their rate at 200 and 400 muM. Furthermore, it significantly prolonged SPWs, reduced their synchrony and reduced the quantity of ripples only at the clinically very high concentration of 400 muM, reported to affect memory.


CONCLUSIONS
We hypothesize that thiopental, by interfering with SPW-R activity, through enhancement of the GABAA receptor-mediated transmission, affects memory processes which involve hippocampal circuit activation. The quantity but not the frequency of ripple oscillation was affected by the drug.
Department of Physiology, Medical School, University of Patras, Rion, Greece. cepapath@med.upatras.gr
Costas
C
Papatheodoropoulos
Evangelos
E
Sotiriou
Dimitrios
D
Kotzadimitriou
Panagiota
P
Drimala
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology*; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D009924:Organ Culture Techniques; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013874:Thiopental / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D013874:Thiopental; D010634:Phenobarbital