Effect of DOV 102,677 on the Volitional Consumption of Ethanol by Myers’ High Ethanol‐Preferring Rat

McMillen, Brian A.; Shank, J. Elizabeth; Jordan, Kirstin B.; Williams, Helen L.; Basile, Anthony S.

doi:10.1111/j.1530-0277.2007.00513.x

Cited by 17 publications

(17 citation statements)

References 30 publications

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“…One published preclinical study describes the effect of the “balanced” triple reuptake inhibitor DOV 102,677 in reducing volitional alcohol consumption in ethanol-preferring rats without decreasing food or water consumption [28]. It should be noted that monoamine reuptake inhibitors have historically performed better in animal models of addiction than in human clinical trials.…”

Section: Other Potential Indications For Triple Reuptake Inhibitorsmentioning

confidence: 99%

Triple Reuptake Inhibitors: The Next Generation of Antidepressants

Marks¹,

Pae²,

Patkar³

2008

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Depression has been associated with impaired neurotransmission of serotonergic, norepinephrinergic, and dopaminergic pathways, although most pharmacologic treatment strategies for depression enhance only serotonin and norepinephrine neurotransmission. Current drug development efforts are aimed at a new class of antidepressants which inhibit the reuptake of all three neurotransmitters in the hope of creating medications with broader efficacy and/or quicker onset of action. The current review explores limitations of presently available antidepressants and the history and premise behind the movement to devise triple reuptake inhibitors. The evidence for and against the claim that broader spectrum agents are more efficacious is discussed. Examples of triple reuptake inhibitors in development are compared, and preclinical and clinical research with these agents to date is described.

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Section: Other Potential Indications For Triple Reuptake Inhibitorsmentioning

confidence: 99%

Triple Reuptake Inhibitors: The Next Generation of Antidepressants

Marks¹,

Pae²,

Patkar³

2008

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“…The ability to modify the levels of multiple monoamine neurotransmitters may be the key to treating alcoholism in a broader population. Of interest, a triple monoamine neurotransmitter uptake inhibitor (NE, 5-HT, and dopamine) DOV 102 677, has been shown to decrease voluntary ethanol intake in an ethanol-preferring rat strain (McMillen et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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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“…Moreover, the abuse potential associated with compounds that inhibit all three transporters (triple reuptake inhibitors) is unclear. These agents have the potential for broad therapeutic use in treating depression (Skolnick and Basile, 2007), pain , obesity (Tizzano et al, 2008), and substance abuse (McMillen et al, 2007).…”

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confidence: 99%

Preclinical Evaluation of the Abuse Potential of the Analgesic Bicifadine

Nicholson

Balster²,

Gołembiowska³

et al. 2009

J Pharmacol Exp Ther

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The abuse liability of the analgesic bicifadine was investigated in animal models used to predict the abuse potential of psychostimulants in humans. Bicifadine, cocaine, d-amphetamine, bupropion, and desipramine were evaluated for the production of cocaine-like discriminative stimulus effects in rats. Cocaine, d-amphetamine, and bupropion dose-dependently and fully substituted for cocaine. Bicifadine and desipramine produced a maximum mean cocaine-lever selection of 80 and 69%, respectively, but doses yielding peak substitution strongly suppressed response rates. Microdialysis studies in normal waking rats indicated that d-amphetamine increased dopamine levels in the nucleus accumbens and striatum to a much greater degree than bicifadine, but bicifadine increased 5-hydroxytryptamine levels in the nucleus accumbens and striatum more than d-amphetamine. Bicifadine was also tested for intravenous self-administration in rhesus monkeys experienced with cocaine administration. Reinforcing effects of bicifadine were observed in only two of four subjects, whereas cocaine, d-amphetamine, and bupropion served as reinforcers in all four monkeys. When evaluated under a progressive ratio procedure, no dose of bicifadine maintained responding to the extent of cocaine, d-amphetamine, or bupropion. The discriminative stimulus effects associated with bicifadine were similar, but not identical, to those of psychostimulants. Although bicifadine maintained self-administration behavior in some subjects, its reinforcing efficacy was very low relative to cocaine, d-amphetamine, and bupropion. These results are consistent with the microdialysis findings of lower dopamine levels and higher 5-hydroxytryptamine levels after administration of bicifadine relative to d-amphetamine. Overall, the current findings support a low abuse potential of bicifadine, more resembling that of antidepressants than psychostimulants.Abnormal levels of the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) have been implicated in the pathogenesis of a variety of neuropsychiatric disorders, including depression, neuropathic pain, obesity, and substance abuse. Compounds that inhibit one or more of the transporters for these monoamine neurotransmitters are used to treat many of these disorders. For example, selective inhibitors of 5-HT reuptake (e.g., fluoxetine, citalopram) are effective, albeit imperfect, therapies for major depressive disorder, generalized anxiety disorder, and obsessive-compulsive disorder (Vaswani et al., 2003). Agents that inhibit both 5-HT (SERT) and NE (NET) transporters (e.g., duloxetine and venlafaxine) not only are used to treat major depressive disorder but also are effective as analgesics, particularly in treating chronic neuropathic pain (Barkin and Barkin, 2005). Selective NET inhibitors (e.g., atomoxetine) are currently being used to treat attention deficit disorder (Kratochvil et al., 2003). Because of the involvement of DA in mesocorticolimbic pathways that subserve reward-and incentive...

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Effect of DOV 102,677 on the Volitional Consumption of Ethanol by Myers’ High Ethanol‐Preferring Rat

Abstract: DOV 102,677 significantly decreased the volitional consumption of ethanol with minimal alterations in the intake of food or on body weight in an ethanol-preferring rat strain, suggesting that triple reuptake inhibitors may find utility in treating alcohol abuse.

Cited by 17 publications

References 30 publications

Triple Reuptake Inhibitors: The Next Generation of Antidepressants

Triple Reuptake Inhibitors: The Next Generation of Antidepressants

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

Preclinical Evaluation of the Abuse Potential of the Analgesic Bicifadine

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