Modulation of long-term potentiation in CA1 region of mouse hippocampal brain slices by GABAA receptor benzodiazepine site ligands.
Enhancement of GABAA receptor function with benzodiazepine (BZ) site agonists can disrupt memory formation and hippocampal synaptic plasticity. To investigate this further the effects of the agonist, flunitrazepam, were contrasted with that of the inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), on NMDA-dependent LTP induction in the CA1 region of mouse hippocampus. Under control conditions, a priming stimulus (10 stimuli at 100 Hz) potentiated e.p.s.p. slopes by 198%, and subsequent burst stimuli (4 x 10 events at 100 Hz every 20 sec) by 306%. This potentiation was blocked by the non-competitive NMDA receptor antagonist MK-801 and the glycine site antagonist L-701,324. Flunitrazepam (1 microM) alone caused a slight but significant reduction in e.p.s.p.s to 83% of control, suppressed LTP induced by priming stimuli (133%) and burst stimuli (188%), but not that induced by sustained high-frequency stimulation (2 x 100 events at 100 Hz, 20 sec apart). The suppression of LTP induction by flunitrazepam was blocked by the benzodiazepine site antagonist flumazenil. In contrast, the inverse agonist DMCM (100 nM) potentiated LTP formed by both priming (to 283%) and burst stimuli (to 477%). This was associated with an enhancement of paired pulse facilitation during the induction phase and the subsequent appearance of paroxysmal burst discharges. Therefore, in addition to improvements in learning and memory as a result of improved vigilance, benzodiazepine inverse agonists can have direct effects on synaptic processes thought to contribute to memory formation.
Seabrook
G R
GR
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, U.K.
Easter
A
A
Dawson
G R
GR
Bowery
B J
BJ
D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D015363:Quinolones / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology
D002243:Carbolines; D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; D015363:Quinolones; D011963:Receptors, GABA-A; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005442:Flumazenil; D005445:Flunitrazepam; D016291:Dizocilpine Maleate; C094635:L 701324