A novel benzodiazepine inverse agonist, S-8510, as a cognitive enhancer

Kawasaki, Kazuo; Eigyo, Masami; Ikeda, Masato; Kihara, Tsuyoshi; Koike, Katsumi; Matsushita, Akira; Murata, Shunji; Shiomi, Teruo; Takada, Susumu; Yasui, Mitsuru

doi:10.1016/s0278-5846(96)00136-4

Cited by 27 publications

(20 citation statements)

References 21 publications

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“…Similarly, some benzodiazepines produce amnesia and diminish LTP in the hippocampus (22). Consistent with these results, benzodiazepine inverse agonists, which can enhance memory function and attenuate amnesia, are found to augment LTP in the hippocampus (23,27). CCK-8 is also known to exert beneficial effects on memory and learning processes following intracerebroventricular administration (10, 11, 13, 14).…”

Section: Effects Of Cck-8 On Paired Pulse Facilitationmentioning

confidence: 67%

CCKB-Receptor Activation Augments the Long-Term Potentiation in Guinea Pig Hippocampal Slices

Yasui

Kawasaki

1995

Japanese Journal of Pharmacology

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ABSTRACT-Effectsof cholecystokinin octapeptide (CCK-8) on long-term potentiation (LTP) of CAI synaptic transmission induced by tetanic stimulation of the input fibers were examined in guinea pig hippocampal slices. CCK-8 and a selective agonist for the CCKB receptor, non-sulfated CCK-8, dose-dependently augmented the magnitude of LTP. Concomitant application of a selective antagonist for the CCKBreceptor subtype, L-365,260completely blocked the augmentation of LTP induced by CCK-8, whereas a selective CCKA-receptor antagonist, L-364,718 (3S(-)-N-(2,3-dihydro-l-methyl-2-oxo-5-phenyl-IH-1,4-benzodiazepine)), had little effect. Thus, enhancement of LTP by CCK appears to be mediated by CCKB receptors. Furthermore, CCK-8 enhanced paired-pulse facilitation at a concentration of 10-7 M without affecting the amplitude of the population spike induced by single stimulation. This effect was mimicked by a low dose of tetraethylammonium (TEA), a K+ channel blocker. Moreover, both CCK-8 and TEA reduced the late component of evoked field potentials. This late evoked potential was diminished by increasing the extracellular K+ concentration. It is suggested that CCK-8 reduces the K+ conductance in CAI pyramidal neurons. This reduction in the K+ conductance might be related to enhancement of the LTP.

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Section: Effects Of Cck-8 On Paired Pulse Facilitationmentioning

confidence: 67%

CCKB-Receptor Activation Augments the Long-Term Potentiation in Guinea Pig Hippocampal Slices

Yasui

Kawasaki

1995

Japanese Journal of Pharmacology

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“…[29][30][31][32] As BZR and neurons measured by FMZ or IMZ are preserved in the early stages of AD, the patients may be treatable with those cognition enhancers having benzodiazepine inverse agonist-like properties. [21][22][23][24][25][26][27][28][29][30][31] It is also suggested that benzodiazepines may have protective effects against AD based on epidemiological evidence of an association between benzodiazepine use and the occurrence of AD and vascular dementia in 668 individuals.…”

Section: Benzodiazepine Receptor In Alzheimermentioning

confidence: 99%

“…Other investigators reported a more prominent reduction in IMZ uptake than CBF decrease measured by HMPAO in patients with AD. 28 As cognition enhancers in relation to benzodiazepine receptors have been proposed as a treatment of AD, [29][30][31][32] in vivo evaluation of BZR is becoming more important.…”

Section: Introductionmentioning

confidence: 99%

Preserved benzodiazepine receptors in Alzheimer’s disease measured with C-11 flumazenil PET and I-123 iomazenil SPECT in comparison with CBF

et al. 1999

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This study evaluates the regional cerebral blood flow (CBF) with H2(15)O-PET and the distribution of central benzodiazepine receptor (BZR) with C-11 flumazenil (FMZ) by PET and I-123 iomazenil (IMZ) by SPECT in Alzheimer's disease (AD). In AD, whereas the CBF was diminished in the frontal, temporal, parietal, and occipital cortex, the distribution volume of FMZ and delayed activity of IMZ were relatively preserved in these cortices, suggesting that the BZR reduction, reflecting neuronal loss, is less prominent than the CBF suppression. The mini-mental state examination score (MMS) was weakly correlated with the CBF in the parietal cortex but not with BZR. It is speculated that the neuronal density reflected by BZR is less impaired than the neuronal function assessed with blood flow in the association cortex of AD. High correlation was found between the uptake of FMZ and the delayed activity of IMZ. The delayed image of IMZ-SPECT is clinically useful to evaluate the preservation of neuronal density in the affected temoporoparietal association cortex in AD.

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“…More specifically, neurochemical data indicate that the hippocampal cholinergic system may be involved in the integration of anxiety and memory. Thus, fluctuations of ACh efflux in the hippocampus are associated with modulations of emotionality and cognition (Egawa et al, 2002;Olariu et al, 2001;Decker et al, 1994;Degroot and Treit, 2002;Kawasaki et al, 1996). Interestingly, benzodiazepines, which decrease anxiety and interfere with aversive memory formation, also decrease hippocampal ACh efflux.…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

Degroot

Nomikos

2004

Neuropsychopharmacol

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Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac s ) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.

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A novel benzodiazepine inverse agonist, S-8510, as a cognitive enhancer

Cited by 27 publications

References 21 publications

CCKB-Receptor Activation Augments the Long-Term Potentiation in Guinea Pig Hippocampal Slices

CCKB-Receptor Activation Augments the Long-Term Potentiation in Guinea Pig Hippocampal Slices

Preserved benzodiazepine receptors in Alzheimer’s disease measured with C-11 flumazenil PET and I-123 iomazenil SPECT in comparison with CBF

Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

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