Desipramine potentiation of the acute depressant effects of ethanol: Modulation by α2-adrenoreceptors and stress

Boyce-Rustay, Janel M.; Palachick, Benjamin; Hefner, Kathryn R.; Chen, Yi-Chyan; Karlsson, Rose−Marie; Millstein, Rachel; Harvey−White, Judith; Holmes, Andrew

doi:10.1016/j.neuropharm.2008.06.032

Cited by 19 publications

(11 citation statements)

References 91 publications

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“…To our knowledge, our study is the first to investigate the effect of a NET inhibitor on ethanol-induced sensitization. A previous study reported that desipramine (30 mg/kg), but not fluoxetine, potentiates the acute hypnotic/sedative effect of ethanol (3.0 g/kg) in mice and that this effect may be mediated via a2-adrenoreceptor (Boyce-Rustay et al, 2008). We provide evidence that fluoxetine has opposite effects depending on sensitization phases.…”

Section: Discussionsupporting

confidence: 55%

Fluoxetine, Desipramine, and the Dual Antidepressant Milnacipran Reduce Alcohol Self-Administration and/or Relapse in Dependent Rats

O'Brien

Legastelois

Houchi

et al. 2011

Neuropsychopharmacol

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A few clinical studies have shown that dual antidepressants (serotonergic (5-HT) and noradrenergic (NE) transporter inhibitors, SNRIs) may be effective in alcoholism treatment. We studied the effect of the dual antidepressant milnacipran on ethanol operant self-administration in acutely withdrawn ethanol-dependent and in -non-dependent Wistar rats, and used fluoxetine and desipramine to dissect both 5-HT and NE components, respectively, in the effect of milnacipran. Milnacipran was also tested for relapse after protracted abstinence and on ethanol-induced (1.0 g/kg) conditioned place preference in control rats and ethanol-induced locomotor sensitization in DBA/2J female mice. Milnacipran dose dependently (5-40 mg/kg) attenuated the increased ethanol self-administration observed during early withdrawal and was more potent in preventing reinstatement in dependent rats after protracted abstinence as compared with non-dependent rats. Desipramine and fluoxetine (10 mg/kg) blocked ethanol self-administration during early withdrawal, and recovery was delayed in dependent animals, indicating a potent effect. Ethanol self-administration was also reduced 1 day after treatment with desipramine and fluoxetine but not with milnacipran. Finally, milnacipran prevented ethanol-induced place preference in ethanol-naive rats and reduced the magnitude of ethanol-induced sensitization associated with a delayed induction in mice. Desipramine (20 mg/kg) countered sensitization development and reduced its expression at 1 week after treatment; fluoxetine (10 mg/kg) reduced sensitization expression. Thus, 5-HT and NE transmissions during sensitization expression may mediate the effect of milnacipran on sensitization induction. These results support that SNRIs may have a potential use in alcoholism treatment.

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Section: Discussionsupporting

confidence: 55%

Fluoxetine, Desipramine, and the Dual Antidepressant Milnacipran Reduce Alcohol Self-Administration and/or Relapse in Dependent Rats

O'Brien

Legastelois

Houchi

et al. 2011

Neuropsychopharmacol

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“…In addition, blockade of NE reuptake with desmethylimipramine (DMI) has long been known to produce hypoactivity in rodents which might be the result of stimulation of postsynaptic α 2 -receptors in forebrain regions by endogenous NE. In agreement, we and others recently found that prior blockade of these receptors with systemic atipamezole in mice attenuates the hypoactivity in mice in the open field after DMI as well as enhances Fos expression throughout the neocortex (Boyce-Rustay et al 2008; Stone, EA and Lin, Y, unpublished observations).…”

Section: Mechanisms For Neural and Behavioral Inhibitionsupporting

confidence: 88%

The role of the central noradrenergic system in behavioral inhibition

Stone

Yang

Sarfraz

et al. 2011

Brain Research Reviews

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Although the central noradrenergic system has been shown to be involved in a number of behavioral and neurophysiological processes, the relation of these to its role in depressive illness has been difficult to define. The present review discusses the hypothesis that one of its chief functions that may be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological and immunohistochemical experiments on active behavior in rodents in a variety of experimental conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic receptors. The findings support a mechanism in which high rates of noradrenergic neural activity suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the release of corticotrophin-releasing hormone. The hypothesis is consistent with clinical evidence for central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural activation may be a unifying function.

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“…In present study, the enhancement of HO-1 expression by desipramine could be regulated by ERK and JNK, but the effect of fluoxetine was only regulated by JNK. Moreover, it has also been reported that the difference in potency between desipramine and fluoxetine exerts in many functions, such as inhibition of chemotaxis on polymorphonuclear leukocytes [79], acute hypnotic/sedative effect of ethanol [80] and development of ethanol-induced behavioral sensitization [81]. Our results reveal that desipramine-enhanced HO-1 expression sustains to 24 h, however, fluoxetine-increased HO-1 expression reaches a peak at 8 h. Our results and previous reports indicate that different types of antidepressant exert different molecular mechanisms which could provide a novel view for clinical drug choice.…”

Section: Discussionmentioning

confidence: 99%

Desipramine Protects Neuronal Cell Death and Induces Heme Oxygenase-1 Expression in Mes23.5 Dopaminergic Neurons

et al. 2012

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BackgroundDesipramine is known principally as a tricyclic antidepressant drug used to promote recovery of depressed patients. It has also been used in a number of other psychiatric and medical conditions. The present study is the first to investigate the neuroprotective effect of desipramine.Methodology/Principal FindingsMes23.5 dopaminergic cells were used to examine neuroprotective effect of desipramine. Western blot, reverse transcription-PCR, MTT assay, siRNA transfection and electrophoretic mobility shift assay (EMSA) were carried out to assess the effects of desipramine. Desipramine induces endogenous anti-oxidative enzyme, heme oxygenase-1 (HO-1) protein and mRNA expression in concentration- and time-dependent manners. A different type of antidepressant SSRI (selective serotonin reuptake inhibitor), fluoxetine also shows similar effects of desipramine on HO-1 expression. Moreover, desipramine induces HO-1 expression through activation of ERK and JNK signaling pathways. Desipramine also increases NF-E2-related factor-2 (Nrf2) accumulation in the nucleus and enhances Nrf2-DNA binding activity. Moreover, desipramine-mediated increase of HO-1 expression is reduced by transfection with siRNA against Nrf2. On the other hand, pretreatment of desipramine protects neuronal cells against rotenone- and 6-hydroxydopamine (6-OHDA)-induced neuronal death. Furthermore, inhibition of HO-1 activity by a HO-1 pharmacological inhibitor, ZnPP IX, attenuates the neuroprotective effect of desipramine. Otherwise, activation of HO-1 activity by HO-1 activator and inducer protect 6-OHDA-induced neuronal death.Conclusions/SignificanceThese findings suggest that desipramine-increased HO-1 expression is mediated by Nrf2 activation through the ERK and JNK signaling pathways. Our results also suggest that desipramine provides a novel effect of neuroprotection, and neurodegenerative process might play an important role in depression disorder.

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Desipramine potentiation of the acute depressant effects of ethanol: Modulation by α2-adrenoreceptors and stress

Cited by 19 publications

References 91 publications

Fluoxetine, Desipramine, and the Dual Antidepressant Milnacipran Reduce Alcohol Self-Administration and/or Relapse in Dependent Rats

Fluoxetine, Desipramine, and the Dual Antidepressant Milnacipran Reduce Alcohol Self-Administration and/or Relapse in Dependent Rats

The role of the central noradrenergic system in behavioral inhibition

Desipramine Protects Neuronal Cell Death and Induces Heme Oxygenase-1 Expression in Mes23.5 Dopaminergic Neurons

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