D'Aquila P, Monleon S, Borsini F, Brain P, Willner P
Department of Psychology, University of Wales, Swansea, UK.
Eur J Pharmacol. 1997 Dec 11;340(2-3):121-32. doi: 10.1016/s0014-2999(97)01412-x.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT1A receptor agonist and 5-HT2 receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D2/D3 receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D2/D3 receptor-mediated transmission.
先前已发现，长期暴露于轻度不可预测应激会降低可口甜味溶液的摄入量，并阻止条件性位置偏好的形成；三环或非典型抗抑郁药物的长期治疗可逆转这些效应。本研究旨在评估氟立班丝氨（BIMT - 17）在该模型中的抗抑郁样活性，氟立班丝氨是一种具有5 - HT1A受体激动剂和5 - HT2受体拮抗剂特性的新型血清素能药物。使用大鼠（实验1）和小鼠（实验2）进行了两项实验。在实验1中，暴露于慢性轻度应激的大鼠蔗糖摄入量减少，但在本研究中该效应不可靠，应激7周后蔗糖测试终止。在应激5周后开始，对照组和应激组动物每天分别用赋形剂、氟西汀（5 mg/kg）或氟立班丝氨（5、10或20 mg/kg）进行处理。治疗6周后，对所有动物进行食物强化位置偏好条件反射获得测试。除用赋形剂处理的应激动物组外，所有组均出现条件反射。我们还测试了单次注射多巴胺D2/D3受体激动剂喹吡罗（0.2 mg/kg）的运动兴奋作用。在对照动物中，喹吡罗的作用被氟西汀增强，在应激动物中，喹吡罗的作用被氟西汀和氟立班丝氨（所有剂量）增强。在实验2中，暴露于慢性轻度应激的小鼠蔗糖摄入量出现持久下降。氟西汀（5 mg/kg）或氟立班丝氨（2.5或5 mg/kg）的慢性（4周）治疗可逆转这些效应；氟立班丝氨在首次注射后即出现完全效应。在药物治疗第27天进行蔗糖摄入量测试前，所有动物均立即单次注射雷氯必利（0.1 mg/kg）。雷氯必利仅在三个药物治疗的应激组中降低了蔗糖摄入量。结果支持氟立班丝氨具有快速抗抑郁样作用，并表明该效应涉及多巴胺D2/D3受体介导的传递的敏化。
