Flumazenil and tacrine increase the effectiveness of ondansetron on scopolamine-induced impairment of spatial learning in rats

Diez-Ariza, M.; Redondo, C.; García-Alloza, Mónica; Lasheras, B.; Rı́o, Joaquı́n Del; Ramı́rez, Marı́a J.

doi:10.1007/s00213-003-1467-1

Cited by 24 publications

(12 citation statements)

References 56 publications

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“…The water maze procedure was adapted (Diez-Ariza et al, 2003) from that described originally (Morris, 1984). The maze consisted of a black circular tank (140 cm in diameter 355 cm high) filled with water at 208C 6 18C.…”

Section: Morris Water Mazementioning

confidence: 99%

Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation

et al. 2011

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Recent evidence suggests that activity-regulated cytoskeleton associated protein (Arc) and brain-derived neurotrophic factor (BDNF) are key players in the cellular mechanisms that trigger synaptic changes and memory consolidation. Cholinergic deafferentiation of hippocampus has been largely shown to induce memory impairments in different behavioral tasks. However, the mechanisms underlying cholinergic-induced memory formation remain unclear. The role of hippocampal cholinergic denervation on synaptic consolidation and further acquisition of spatial memory was hereby examined by analyzing Arc and BDNF in standard environment and after behavioral training in Morris water maze (MWM). In standard environment, a cholinergic hypofunction induced by the toxin (192) IgG-saporin led to significant decreases in Arc protein and mRNA as well as in BDNF. Lesioned rats subjected to MWM showed a worse acquisition performance that was reversed after galantamine treatment. Recovery of memory acquisition was accompanied by normalization of Arc and BDNF levels in hippocampus. Stimulation of muscarinic, but not nicotinic receptors, in hippocampal primary neurons caused a rapid induction of Arc production. These data suggest that cholinergic denervation of hippocampus leads to deficits in muscarinic-dependent induction of Arc and a subsequent impairment of spatial memory acquisition.

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Section: Morris Water Mazementioning

confidence: 99%

Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation

et al. 2011

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“…The water maze procedure was adapted (Diez-Ariza et al, 2003) from that described originally (Morris, 1984). The maze consisted of a black circular tank (140 cm diameter 3 55 cm high) and filled with water (20-228C).…”

Section: Morris Water Mazementioning

confidence: 99%

Effects of neonatal stress on markers of synaptic plasticity in the hippocampus: Implications for spatial memory

et al. 2009

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Early stressful adverse situations may increase the vulnerability to cognitive deficits and psychiatric disorders, such as depression. Maternal separation (MS) has been used as an animal model to study changes in neurochemistry and behavior associated with exposure to early-life stress. This study investigated the effects of neonatal stress (MS) on the expression of synaptic plasticity markers in the hippocampus and a purported relationship to cognitive processes. Spatial learning (Morris water maze) significantly increased the expression of total levels of the neural cell adhesion molecule (NCAM), as well as its three major isoforms (NCAM-120, -140, and -180) both in the control and MS groups. Interestingly, these increases in NCAM expression after learning were lower in MS animals when compared with control rats. MS induced a significant decrease in total levels of NCAM, and specifically, in the NCAM-140 isoform expression. In the hippocampus of MS rats there was a significant decrease in brain-derived neurotrophic factor and synaptophysin mRNA densities. Cell proliferation, measured as BrdU-positive cells, was also decreased in the dentate gyrus of MS rats. Altogether these results suggest that MS can alter normal brain development, providing a potential mechanism by which early environmental stressors may influence vulnerability to show cognitive impairments later in life.

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“…The question about the responsiveness of neurons surviving lesions to the combined treatment was addressed next. The doses of drugs used were selected according to our previous studies, in which the combined treatment with ondansetron, 0.1 lg/kg, and flumazenil, 10 mg/kg, showed a maximal effect on cortical ACh release ''in vivo'' (Diez-Ariza et al, 2002) and was able to reverse scopolamine-induced learning (Diez-Ariza et al, 2003). Interestingly, and at both 7 and 30 days after lesion, concomitant administration of ondansetron with flumazenil significantly increased ACh release (expressed as maximum release, cumulated release or AUC) even though single treatment with either drug was ineffective.…”

Section: Discussionmentioning

confidence: 99%

Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation

et al. 2004

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We have studied the effects of concomitant blockade of 5-HT 3 and GABA A receptors on acetylcholine (ACh) release in the frontal cortex of rats with a selective cholinergic lesion. Lesions were performed by microinjection of the cholinergic toxin 192 IgG-saporin into the nucleus basalis magnocellularis. Single treatment with either the 5-HT 3 receptor antagonist ondansetron, 0.1 lg/kg, or the GABA A receptor benzodiazepine site antagonist flumazenil, 10 mg/kg, did not affect ACh release. However, the combined ondansetron þ flumazenil administration significantly increased ACh release to a similar extent as a depolarising stimulus with K + , 100 mM, at both 7 and 30 days post-lesion. Cortical perfusion with the combined ondansetron þ flumazenil treatment also increased [ 3 H]ACh efflux ''in vitro'' 30 days after lesion, suggesting that local events within the frontal cortex may participate in the interaction of ondansetron with GABAergic neurons, modulating ACh release in situations of cholinergic hypoactivity. No differences in the expression of 5-HT 3 and GABA A receptors in the frontal cortex were found after the cholinergic lesion. These results suggest that a combined ondansetron þ flumazenil treatment would contribute to restoring a diminished cholinergic function and may provide a basis for using this treatment in the therapy of cognitive disorders associated with degeneration of the cholinergic system. #

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Flumazenil and tacrine increase the effectiveness of ondansetron on scopolamine-induced impairment of spatial learning in rats

Cited by 24 publications

References 56 publications

Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation

Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation

Effects of neonatal stress on markers of synaptic plasticity in the hippocampus: Implications for spatial memory

Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation

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