Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and α1-adrenoceptors

Tachibana, Kaori; Matsumoto, Machiko; Togashi, Hiroko; Kojima, Taku; Morimoto, Yuji; Kemmotsu, Osamu; Yoshioka, Mitsuhiro

doi:10.1016/j.neulet.2003.11.016

Cited by 37 publications

(24 citation statements)

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“…Imipramine in particular has been used as a antidepressant/anxiolytic agent [47]. In our results, milnacipran showed anxiolytic-like effects in the chronic treatment probably due to functional interaction between the serotonergic and noradrenergic neuronal systems induced by milnacipran [48][49][50].…”

Section: Discussionsupporting

confidence: 51%

Effects of Milnacipran in Animal Models of Anxiety and Memory

et al. 2006

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Serotonin (5-HT) and noradrenaline (NA) are involved in both pathogenesis and recovery from depression and anxiety. We examined the effects of acute and chronic treatment with milnacipran, a serotonin/noradrenaline reuptake inhibitors (SNRIs) antidepressant, on anxiety and memory retention in rats. Male Wistar rats received acute or chronic administration of milnacipran (12.5, 25 or 50 mg/kg) or saline (control group). The animals were separately submitted to elevated plus-maze, inhibitory avoidance and open-field tasks 1 h after injection, in the acute group, or 23 h after last injection, in the chronic group. Our results showed an anxiolytic-like effect after chronic administration of milnacipran at doses of 25 and 50 mg/kg. The treatment does not interfere in memory retention and habituation to a novel environment at any doses studied. These findings support that milnacipran, an established SNRIs antidepressant, can also be useful in the treatment of anxiety disorders.

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Section: Discussionsupporting

confidence: 51%

Effects of Milnacipran in Animal Models of Anxiety and Memory

et al. 2006

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“…Furthermore, milnacipran suppressed the longterm potentiation in the hippocampal CA1 field of anesthetized rats [21]. Anatomically, the hippocampal CA1 region gives rise to projections to the nucleus accumbens shell and infralimbic cortex [22], both of where Fos counts were decreased in the present study.…”

Section: Discussionsupporting

confidence: 51%

Neural Activation by Milnacipran and Memory Extinction

Ishida¹,

Iwata²,

Shirayama³

et al. 2012

JBBS

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Background: Among neurotransmitter influencing memory formation, the noradrenergic system has been recognized as an important system. Memory formation involves various regions including the prefrontal cortex, hippocampus, amygdala and septum. Method: We investigated the effects of milnacipran on passive avoidance task and evaluated Fos counting in the prefrontal cortex, hippocampus, septum, amygdala and nucleus accumbens. Results: The milnacipran-treated rats (20 mg/kg, 4 days) showed a significant decrease in the number of Fos-immunoreactive cells in the infralimbic portion of prefrontal cortex, the shell portion of nucleus accumbens and the CA1 region of hippocampus, but a significant increase in the Fos counts in the lateral septum with no changes in the Fos counts in the striatum and amygdala. The milnacipran-treated rats showed amelioration in memory extinction (although not statistically significant), but not in memory acquisition and consolidation in the passive avoidance test. Conclusion: The differential activation of the brain regions might be possible sites for ameliorating memory extinction as well as antidepressant effects.

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“…Although depletion of serotonin is reported to attenuate perforant path-dentate gyrus LTP in intact animals (Bliss et al 1983), LTP induction in the dentate gyrus is not altered in hippocampal slices taken from serotonin-depleted animals (Stanton and Sarvey 1985). In addition, 5-HT1a receptor activation generally has an inhibitory effect on LTP at perforant path-dentate synapses in vitro (Sakai and Tanaka 1993;Kojima et al 2003;Tachibana et al 2004). These effects may reflect an attenuation of LTP via the 5-HT1a receptormediated hyperpolarization observed in principal cells of the hippocampal formation (Segal 1990;Piguet and Galvan 1994;Gulyás et al 1999).…”

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confidence: 99%

5-HT1a receptor antagonists block perforant path-dentate LTP induced in novel, but not familiar, environments

et al. 2006

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Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated enhancement of LTP. In freely moving animals, systemic administration of the selective 5-HT1a antagonist WAY-100635 (WAY) attenuated LTP in a dose-dependent manner when LTP was induced while animals explored novel cages. In contrast, LTP was completely unaffected by WAY when induced in familiar environments. LTP was also blocked in anesthetized animals by direct application of WAY to the dentate gyrus, but not to the median raphe nucleus (MRN), suggesting the effect of systemic WAY is mediated by a block of dentate 5-HT1a receptors. Paradoxically, systemic administration of the 5-HT1a agonist 8-OH-DPAT also attenuated LTP. This attenuation was mimicked in anesthetized animals following application of 8-OH-DPAT to the MRN, but not the dentate gyrus. In addition, application of a 5-HT1a agonist to the dentate gyrus reduced somatic GABAergic inhibition. Because serotonergic projections from the MRN terminate on dentate inhibitory interneurons, these data suggest 5-HT1a receptors contribute to LTP induction via inhibition of GABAergic interneurons. Moreover, activation of raphe 5-HT1a autoreceptors, which inhibits serotonin release, attenuated LTP induction even in familiar environments. This suggests that serotonin normally contributes to dentate LTP induction in a variety of behavioral states. Together, these data suggest that serotonin and dentate 5-HT1a receptors play a permissive role in dentate LTP induction, particularly in novel conditions, and presumably, during the encoding of novel, hippocampus-relevant information.Long-term potentiation (LTP) remains the most intensively studied model of the cellular mechanisms of synaptic plasticity that may underlie memory (Bliss and Lomo 1973;Bliss and Collingridge 1993). Previously, we and others reported that the magnitude and longevity of LTP is enhanced when LTP is induced while animals explore novel environments, suggesting that behavioral states that involve novelty, and presumably learning, are optimal for synaptic plasticity (Davis and Derrick 1997;Straube et al. 2003a;Davis et al. 2004; Kemp and ManahanVaughan 2004). In line with this finding, it is suggested that novelty engages the hippocampal formation in a distinct "mode" of operation that appears optimal for inducing synaptic plasticity, and presumably, encoding (Buzsaki 1989;Paulsen and Moser 1998;Vinogradova 2001;Hasselmo et al. 2002;Lisman and Otmakhova 2002;Davis et al. 2004;Guzowski et al. 2004).A number of studies suggest that the enhancement of LTP by novelty is mediated by monoaminergic neuromodulators (Bramham et al. 1997;Paulsen and Moser 1998;Li et al. 2003; Straube et al. 2005b). Previous studies strongly support roles for both norepinephrine (Kitchi...

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Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and α1-adrenoceptors

Cited by 37 publications

References 17 publications

Effects of Milnacipran in Animal Models of Anxiety and Memory

Effects of Milnacipran in Animal Models of Anxiety and Memory

Neural Activation by Milnacipran and Memory Extinction

5-HT1a receptor antagonists block perforant path-dentate LTP induced in novel, but not familiar, environments

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