Because of clinical interest in the effects of antidepressant drugs that exert their effects on multiple neurotransmitter systems, the behavioral effects produced by combined treatment with an SSRI (fluoxetine) with a selective norepinephrine (NE; desipramine) or dopamine (DA) reuptake inhibitor (buproprion) were examined in the forced swimming test (FST), a behavioral test in rodents that predicts the clinical activity of antidepressants. Three additional compounds with mixed activity as NE-5-HT reuptake inhibitors, milnacipran, duloxetine and venlafaxine, were also examined. Desipramine and fluoxetine both reduced immobility in the FST, but desipramine increased only climbing behavior, whereas fluoxetine increased only swimming behavior. The combination of fluoxetine with desipramine or bupropion increased both climbing and swimming behaviors at certain doses, but higher doses of desipramine when combined with fluoxetine replaced swimming behavior with climbing behavior. The mixed NE-5-HT reuptake inhibitors milnacipran and duloxetine reduced immobility and increased climbing behavior, but did not alter swimming. Venlafaxine reduced immobility and increased swimming behavior, except at the highest dose tested (80 mg/kg), which increased both swimming and climbing behaviors. Thus, combining certain doses of pharmacologically selective monoamine reuptake inhibitors, or the mixed reuptake inhibitor venlafaxine, produced a pattern of mixed active behaviors in the FST (climbing and swimming) that may reflect the activity of multiple neurotransmitters, especially the combination of enhanced 5-HT and DA activity. The combination of higher doses of desipramine with fluoxetine, or compounds with mixed activity at inhibiting NE and 5-HT reuptake, demonstrated effects similar to those of desipramine alone and may reflect inhibition of the expression of serotonergic antidepressant behavioral effects by selective NE reuptake inhibitors.

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 ␣ 2 -adrenoreceptors and 5-HT 1A -receptors have important regulatory functions and are involved in 5-HT/NA interactions, we examined whether the ␣ 2 -receptorantagonist 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 ϩ fluoxetine (10/10 mg/kg), or the dual serotonin/ noradrenaline reuptake-inhibitor milnacipran (20 mg/kg). (b) 8-OH- (Porsolt et al. 1977(Porsolt et al. , 1978(Porsolt et al. , 1979, which detects all the major classes of antidepressant treatments (Borsini and Meli 1988) NO . 4 (MAOIs), atypical antidepressants, and electroconvulsive shock. The FST is also used to investigate the mechanisms of action of antidepressant drugs (Borsini 1995) or the functional interactions that occur when antidepressants are administered (Redrobe and Bourin 1999;Rénéric and Lucki 1998). The rat FST consists of placing the animal in a jar filled with water for a pre-test on day 1, and for a five-minute test session 24 hours later, with the drugs being administered sub-acutely (3 injections) between the two sessions. The animal first attempts to escape and then progressively adopts an immobile posture, making only small movements to keep its head above water. Effective antidepressant treatments decrease the duration of immobility in the test session (Porsolt et al. 1978). Other methods of scoring the FST take into account swimming and climbing, two main active behaviors occurring in the test, which contribute to the antidepressant-like decrease in immobility-duration (Detke et al. 1995b). This procedure showed that noradrenaline (NA)-reuptake inhibitors (NRIs) and selective serotonin (5-hydroxytryptamine/ 5-HT)-reuptake inhibitors (SSRIs) increased selectively and respectively climbing and swimming behavior (Detke et al. 1995b). This technique can thus distinguish components to the behavioral response to antidepressants (Lucki 1997), which is in agreement with distinguishable neurochemical and behavioral contributions to the therapeutic effects of antidepressants in humans (Heninger et al. 1996;Katz et al. 1994).Serotonin and noradrenaline systems are directly involved in the pathogenesis and the recovery from depression (Blier et al. 1990;Caldecott Hazard et al. 1991), and there were clinical suggestions that...

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