In the rat forced swimming test, chronic but not subacute administration of dual 5-HT/NA antidepressant treatments may produce greater effects than selective drugs.
The rat forced swimming test (FST) distinguishes selective serotonin (5-HT) and selective noradrenaline (NA) reuptake-inhibitors, which respectively increase swimming and climbing behaviours. However, NA-system-mediated inhibition of 5-HT-induced swimming prevents dual 5-HT/NA reuptake-inhibition to produce concurrently climbing with swimming. Since adaptative neurochemical processes occur in the treatment of depression, we examined the influence of long-term antidepressant treatment on these interactions.


METHODS
(1) Selective [fluoxetine: 10 mg/kg; desipramine: 10 mg/kg] and non-selective [milnacipran: 40 mg/kg; mirtazapine: 20 mg/kg] antidepressants were administered subacutely (3inj) and chronically (17inj) over 16 days. (2) A subacute fluoxetine-desipramine combination (10-10 mg/kg) was administered in rats that were pre-treated with chronic-desipramine (10 mg/kg per day, 14 days). (3) NA-system-mediated interactions were further examined by combining the alpha(2)-receptor agonist clonidine (5, 10, 20, 200 microg/kg) with 10 mg/kg fluoxetine.


RESULTS
(1) Long-term treatment with either fluoxetine or desipramine does not modify the behavioural response produced by their subacute administration. (2) In contrast, whereas subacute-milnacipran increases climbing solely, chronic-milnacipran produces greater anti-immobility effects and increases both climbing and swimming behaviours. Similarly, the fluoxetine-desipramine combination produces climbing solely, but increases both climbing and swimming behaviours in animals pre-treated with chronic-desipramine. Chronic but not subacute-mirtazapine increases swimming behaviour. (3) clonidine dose-dependently antagonizes fluoxetine-induced anti-immobility effects and swimming behaviour.


CONCLUSIONS
Chronic enhancement of NA-transmission alters NA-system-mediated inhibition of 5-HT-induced behaviour in the FST, which may involve alpha(2)-receptors.
Rénéric
Jean-Philippe
JP
Laboratoire de Neuropsychobiologie des Désadaptations, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5541, BP31, Université Bordeaux II, 33076 Bordeaux Cedex, France. jean-philippe.reneric@labopsy.u-brodeaux2.fr
Bouvard
Manuel
M
Stinus
Luis
L
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D003521:Cyclopropanes / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000523:psychology*; D003891:Desipramine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005473:Fluoxetine / Q000627:therapeutic use; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000078764:Milnacipran; D000078785:Mirtazapine; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013550:Swimming / Q000523:psychology*
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D018687:Antidepressive Agents, Second-Generation; D003000:Clonidine; D003521:Cyclopropanes; D003891:Desipramine; D005473:Fluoxetine; D008803:Mianserin; D000078764:Milnacipran; D000078785:Mirtazapine; D009638:Norepinephrine; D018341:Receptors, Adrenergic, alpha-2; D017367:Selective Serotonin Reuptake Inhibitors