In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed

Rénéric, Jean-Philippe; Bouvard, Manuel; Stinus, Luis

doi:10.1016/s0924-977x(02)00007-x

Cited by 36 publications

(17 citation statements)

References 70 publications

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“…Interestingly, the marked reduction of immobility produced by reboxetine+mirtazapine and its combination with citalopram was obtained with doses of both drugs that are ineffective when given alone, in agreement with data in the literature (Connor et al, 1999;Mague et al, 2003;Reneric et al, 2002). This further supports the above interpretation of the mechanism of action, likely resulting from a synergistic interaction between NET blockade and α 2 -adrenoceptor blockade.…”

Section: Discussionsupporting

confidence: 88%

Noradrenergic antidepressants increase cortical dopamine: Potential use in augmentation strategies

et al. 2012

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Most antidepressant treatments, based on serotonin (5-HT) and/or norepinephrine (NE) transporter blockade, show limited efficacy and slow onset of action, requiring the use of augmentation strategies. Here we report on a novel antidepressant strategy to selectively increase DA function in prefrontal cortex (PFC) without the potential tolerance problems associated to DA transporter blockade. This approach is based on previous observations indicating that extracellular DA in rat medial PFC (mPFC) -but not in nucleus accumbens (NAc)-arises from noradrenergic terminals and is sensitive to noradrenergic drugs. A low dose of reboxetine (3 mg/kg i.p.; NE reuptake inhibitor) nonsignificantly increased extracellular DA in mPFC. Interestingly, its combined administration with 5 mg/kg s.c. mirtazapine (non-selective α2-adrenoceptor antagonist) increased extracellular DA in mPFC (264±28%), but not in NAc. Extracellular NE (but not 5-HT) in mPFC was also enhanced by the combined treatment (472±70%). Repeated (x3) reboxetine+mirtazapine administration produced a moderate additional increase in mPFC DA and markedly reduced the immobility time (-51%) in the forced-swim test. Neurochemical and behavioral effects of the reboxetine+mirtazapine combination persisted in rats pretreated with citalopram (3 mg/kg, s.c.), suggesting its potential usefulness to augment SSRI effects. In situ hybridization c-fos studies were performed to examine the brain areas involved in the above antidepressant-like effects, showing changes in c-fos expression in hippocampal and cortical areas. BDNF expression was also increased in the hippocampal formation. Overall, these results indicate a synergistic effect of the reboxetine+mirtazapine combination to increase DA and NE function in mPFC and to evoke robust antidepressant-like responses.Dear Dr. Frenguelli, I have uploaded a manuscript we would like to submit for publication in Neuropharmacology.The study reports on very marked antidepressant properties of a combination of two commercially available drugs, reboxetine and mirtazapine. The study is based on the recent observation by our group that noradrenergic drugs selectively increase dopamine release in prefrontal cortex. This finding likely derives from the fact that a large proportion of dopamine release in prefrontal cortex arises from noradrenergic axons, being sensitive to NET and alpha2-adrenoceptor blockade. Here we used reboxetine and mirtazapine, , targeting NET and alpha2-adrenoceptors, respectively, to synergistically increase cortical dopaminergic neurotransmission, circumventing the tolerance problems derived from DAT blockade in ventral striatum. (N. Accumbens).The results show that this drug combination evokes marked changes in preclinical variables predictive of clinical antidepressant effects, such as an increase of NA and DA release in prefrontal cortex (but not in N. accumbens) and a marked reduction in immobility in the forced swim test. Neither effect was obtained with either drug alone, indicating a synergistic intera...

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Section: Discussionsupporting

confidence: 88%

Noradrenergic antidepressants increase cortical dopamine: Potential use in augmentation strategies

et al. 2012

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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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“…Hipp, hippocampus; CP, caudate putamen; Hyp, hypothalamus; other abbreviations are as indicated in the text noted that the antidepressant effects of SNRIs involve noradrenergic modulation of 5-HT neuronal function via the desensitization of a 2 adrenoceptors on the terminals of 5-HT neurons [52,[107][108][109] rather than the facilitation of noradrenergic neurotransmission. Furthermore, it has been demonstrated that milnacipran reduced immobility time in NA-depleted rats [52], suggesting that milnacipran could exert 5-HT-related antidepressive effects in addition to causing alterations to NA metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it has been demonstrated that milnacipran reduced immobility time in NA-depleted rats [52], suggesting that milnacipran could exert 5-HT-related antidepressive effects in addition to causing alterations to NA metabolism. It is interesting that changes in NA levels were observed in two DA-related areas in this study: in the NAc after duloxetine treatment, and in the VTA after venlafaxine and sertraline treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The dose of milnacipran used in this study, 20 mg/kg, has been shown to improve depression-like behavior in animal studies [48,49], although higher doses have sometimes been used [50][51][52]. Duloxetine hydrochloride, venlafaxine hydrochloride, milnacipran hydrochloride and sertraline hydrochloride were kindly supplied by Eli Lilly & Co., Wyeth-Ayerst Research, Asahi-Kasei Co. and Pfizer Inc., respectively.…”

Section: Animals and Treatment Proceduresmentioning

confidence: 99%

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Brain Region-Specific Effects of Short-Term Treatment with Duloxetine, Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

et al. 2008

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We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.

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In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed

Cited by 36 publications

References 70 publications

Noradrenergic antidepressants increase cortical dopamine: Potential use in augmentation strategies

Noradrenergic antidepressants increase cortical dopamine: Potential use in augmentation strategies

Effects of Milnacipran in Animal Models of Anxiety and Memory

Brain Region-Specific Effects of Short-Term Treatment with Duloxetine, Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

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