Rénéric J P, Lucki I
Department of Psychiatry, University of Pennsylvania, Philadelphia 19104-2648, USA.
Psychopharmacology (Berl). 1998 Mar;136(2):190-7. doi: 10.1007/s002130050555.
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.
由于临床上对抗抑郁药物作用于多种神经递质系统的效果感兴趣，因此在强迫游泳试验（FST）中研究了选择性5-羟色胺再摄取抑制剂（SSRI，氟西汀）与选择性去甲肾上腺素（NE；地昔帕明）或多巴胺（DA）再摄取抑制剂（安非他酮）联合治疗所产生的行为效应，该试验是一种预测抗抑郁药临床活性的啮齿类动物行为试验。还研究了另外三种具有NE-5-HT再摄取抑制混合活性的化合物，米那普明、度洛西汀和文拉法辛。地昔帕明和氟西汀均可减少FST中的不动时间，但地昔帕明仅增加攀爬行为，而氟西汀仅增加游泳行为。氟西汀与地昔帕明或安非他酮联合使用在某些剂量下可同时增加攀爬和游泳行为，但与氟西汀联合使用时较高剂量的地昔帕明会使游泳行为被攀爬行为取代。混合NE-5-HT再摄取抑制剂米那普明和度洛西汀可减少不动时间并增加攀爬行为，但不改变游泳行为。文拉法辛可减少不动时间并增加游泳行为，但在测试的最高剂量（80mg/kg）时除外，该剂量可同时增加游泳和攀爬行为。因此，联合使用某些剂量的药理选择性单胺再摄取抑制剂或混合再摄取抑制剂文拉法辛，在FST中产生了混合的主动行为模式（攀爬和游泳），这可能反映了多种神经递质的活性，尤其是增强的5-HT和DA活性的联合作用。高剂量地昔帕明与氟西汀联合使用，或在抑制NE和5-HT再摄取方面具有混合活性的化合物，其作用类似于单独使用地昔帕明，可能反映了选择性NE再摄取抑制剂对5-羟色胺能抗抑郁行为效应表达的抑制作用。
