Idazoxan and 8-OH-DPAT Modify the Behavioral Effects Induced by Either NA, or 5-HT, or Dual NA/5-HT Reuptake Inhibition in the Rat Forced Swimming Test

Reneric, J P; Bouvard, Manuel; Stinus, Luis

doi:10.1016/s0893-133x(00)00214-1

Cited by 52 publications

(25 citation statements)

References 60 publications

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“…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. Furthermore, the present results agree with previous studies showing that the combination of desipramine (NET inhibitor) + idazoxan (α 2 -adrenenoceptor antagonist) + fluoxetine (SERT inhibitor) produced a greater reduction of the immobility time, as well an increase of swimming and climbing behaviors (Reneric et al, 2001). …”

Section: Discussionsupporting

confidence: 93%

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: 93%

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: 50%

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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“…Although multiple 5-HT receptors may be involved in antidepressant behavioral responses, activation of postsynaptic 5-HT 1A receptors appears to be important for producing behavioral effects of SSRIs in antidepressant tests De Vry, 1995). Pretreatment with 5-HT 1A receptor partial agonists or antagonists, or genetic deletion of 5-HT 1A receptors can prevent the behavioral effects of SSRIs (Singh and Lucki, 1993;Redrobe and Bourin, 1998;Mayorga et al, 2001;Reneric et al, 2001). Thus, although the 5-HT 1A receptor partial agonist component of EMD 68843 may enhance extracellular 5-HT levels, at high doses it could also restrain expression of antidepressantlike behaviors in the FST, which predict clinical activity.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and Neurochemical Effects of 5-{4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide (EMD 68843): A Combined Selective Inhibitor of Serotonin Reuptake and 5-Hydroxytryptamine_1A Receptor Partial Agonist

Page¹,

Cryan²,

Sullivan³

et al. 2002

J Pharmacol Exp Ther

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5-{4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide (EMD 68843; vilazodone) is a novel compound with combined high affinity and selectivity for the 5-hydroxytryptamine (5-HT) transporter and 5-HT 1A receptors. EMD 68843 was tested as a prototype compound, which benefits from dual pharmacological effects that could increase extracellular 5-HT to levels higher than those produced by conventional selective serotonin reuptake inhibitors (SSRIs). In Sf9 cells, EMD 68843 increased guanosine 5Ј-O-(3-[35 S]thiotriphosphate) binding to 69% of the magnitude of the full 5-HT 1A receptor agonist R-(1) -trans-8-hydroxy-2-[N-n-propyl-N-(39-iodo-29-propenyl)] aminotetralin (8-OH-PIPAT), indicating that it is a partial agonist at 5-HT 1A receptors. Acute, systemic administration of EMD 68843 produced a larger maximal increase of extracellular 5-HT than the SSRI fluoxetine in both the ventral hippocampus (HPv) (558 versus 274%) and the frontal cortex (FC) (527 versus 165%). Regional differences in the response to the two drugs were also observed. These effects may be attributed to the differential regulation of 5-HT release in the HPv and FC by 5-HT 1A autoreceptors. When challenged with the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), EMD 68843-induced increases in extracellular 5-HT were greatly reduced in the HPv but to a lesser extent in the FC. In behavioral studies, EMD 68843 produced antidepressant-like effects in the forced swimming test in both rats and mice but only within a narrow dosage range. Like fluoxetine, EMD 68843 did not produce the symptoms of the 5-HT behavioral syndrome in rats but, unlike fluoxetine, pretreatment with EMD 68843 blocked expression of the 5-HT behavioral syndrome induced by 8-OH-DPAT. Taken together, the results show that EMD 68843 augments extracellular 5-HT levels in forebrain regions to a greater extent than fluoxetine. At higher doses, however, weak efficacy of EMD 68843 at postsynaptic 5-HT 1A receptors may inhibit the expression of rodent antidepressant-like behaviors.Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed class of antidepressant drugs because they are clinically effective, elicit fewer aversive side effects, and have an increased safety margin compared with other antidepressants. SSRIs given acutely block the serotonin transporter and increase extracellular levels of 5-HT in forebrain regions, including the cortex, hippocampus, and striatum (Kreiss and

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Idazoxan and 8-OH-DPAT Modify the Behavioral Effects Induced by Either NA, or 5-HT, or Dual NA/5-HT Reuptake Inhibition in the Rat Forced Swimming Test

Cited by 52 publications

References 60 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

Behavioral and Neurochemical Effects of 5-{4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide (EMD 68843): A Combined Selective Inhibitor of Serotonin Reuptake and 5-Hydroxytryptamine_1A Receptor Partial Agonist

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Idazoxan and 8-OH-DPAT Modify the Behavioral Effects Induced by Either NA, or 5-HT, or Dual NA/5-HT Reuptake Inhibition in the Rat Forced Swimming Test

Cited by 52 publications

References 60 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

Behavioral and Neurochemical Effects of 5-{4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide (EMD 68843): A Combined Selective Inhibitor of Serotonin Reuptake and 5-Hydroxytryptamine1A Receptor Partial Agonist

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Behavioral and Neurochemical Effects of 5-{4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide (EMD 68843): A Combined Selective Inhibitor of Serotonin Reuptake and 5-Hydroxytryptamine_1A Receptor Partial Agonist