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.

The rat forced swimming test (FST) predicts the efficacy of antidepressants, which decrease immobility duration in the test, and can distinguish selective serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors, which, respectively, increase swimming and climbing behaviors. However, dual 5-HT and NA reuptake-inhibition produces climbing behavior solely, thereby suggesting with other data that the NA-system mediates inhibiting interactions on 5-HT-induced swimming in the FST. Since alpha(2)-adrenoreceptors and 5-HT(1A)-receptors have important regulatory functions and are involved in 5-HT/NA interactions, we examined whether the alpha(2)-receptor-antagonist idazoxan and the 5-HT(1A)-receptor-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) would modify the behavioral pattern induced in the FST by either selective or non-selective antidepressant treatments. The rats were treated subacutely (3 injections IP over 48 h) with: (a) idazoxan (0.5-10 mg/kg) alone, and in combination with desipramine (10 mg/kg), or desipramine + fluoxetine (10/10 mg/kg), or the dual serotonin/noradrenaline reuptake-inhibitor milnacipran (20 mg/kg). (b) 8-OH-DPAT (0.25-1 mg/kg) alone, and in combination with either desipramine (10 mg/kg) or fluoxetine (10 mg/kg). The results indicated: (a) Idazoxan (0.5, 5, 10 mg/kg) produced no anti-immobility effects per se in the FST, antagonized the effects of the NA-reuptake-inhibitor desipramine, and allowed desipramine + fluoxetine, as well as milnacipran, to increase swimming behavior. (b) 8-OH-DPAT produced non-significant effects per se, potentiated desipramine-induced antidepressant-like effects on immobility and climbing, and both antagonized swimming and produced climbing behavior in combination with fluoxetine. Our data support clinical trials suggesting that alpha(2)-receptor-antagonists and 5-HT(1A)-receptor-agonists may be of interest in augmentation strategies for antidepressant treatments. The scoring of active behaviors in the FST appears to be an interesting tool for studying 5-HT/NA interactions induced by antidepressants, as well as for the testing of augmentation strategies.