title: Fluoxetine, desipramine, and the dual antidepressant milnacipran reduce alcohol self-administration and/or relapse in dependent rats.
abstract: 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 We studied the effect of the dual antidepressant milnacipran on ethanol operant self-administration in acutely withdrawn ethanol-dependent and in -non-dependent Wistar rats, and used fluoxetine and desipramine to dissect both 5-HT and NE components, respectively, in the effect of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.
authors: Equipe Région INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Faculté de Pharmacie, Amiens, France.
authors: Emmanuelle
authors: E
authors: Simon O'Brien
authors: Rémi
authors: R
authors: Legastelois
authors: Hakim
authors: H
authors: Houchi
authors: Catherine
authors: C
authors: Vilpoux
authors: Stéphanie
authors: S
authors: Alaux-Cantin
authors: Olivier
authors: O
authors: Pierrefiche
authors: Etienne
authors: E
authors: André
authors: Mickaël
authors: M
authors: Naassila
mesh_terms: D000437:Alcoholism / Q000150:complications / Q000188:drug therapy* / Q000523:psychology*; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003521:Cyclopropanes / Q000627:therapeutic use; D003891:Desipramine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D000078764:Milnacipran; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration / Q000295:instrumentation
chemical_list: D000928:Antidepressive Agents; D002492:Central Nervous System Depressants; D003521:Cyclopropanes; D005473:Fluoxetine; D000431:Ethanol; D000078764:Milnacipran; D003891:Desipramine