Kitada Y, Miyauchi T, Kosasa T, Satoh S
Naunyn Schmiedebergs Arch Pharmacol. 1986 May;333(1):31-5. doi: 10.1007/BF00569656.
The present studies were undertaken to clarify whether central beta-adrenoceptor down regulation is responsible for the greater effect of chronic treatment with desipramine (DMI) compared with acute treatment in the forced swimming test in rats. Repetitive administration of DMI activated the rat behaviour pattern and consequently reduced the duration of immobility. The degree of activation depended on the length of treatment, i.e. no effect when given in a single dose, moderate effect when given subchronically (3 doses) and marked activation after chronic (31 doses) treatment. Chronic treatment with DMI also produced a decrease in 3H-dihydroalprenolol (3H-DHA) binding site in the cerebral cortex. Acute stimulation of brain beta-adrenoceptors by intracerebroventricular (i.c.v.) isoprenaline significantly, though partially, attenuated the behavioural effect of chronic DMI by beta 1-adrenoceptor-related mechanisms. Similarly, chronic i.c.v. co-administration of atenolol or practolol, beta 1-adrenoceptor antagonists, together with DMI attenuated both beta-adrenoceptor down regulation and the behavioural activation by chronic DMI. On the other hand, chronic i.c.v. administration of isoprenaline, supposedly leading to down regulation of beta-adrenoceptors, facilitated the activating behavioural effect of DMI, as a single dose became effective. Changes, however, in 3H-DHA binding parameters in the cerebral cortex were not observed after chronic isoprenaline. These results suggest that down regulation of beta-adrenoceptors in brain is responsible, at least in part, for the marked activatory effect of chronic DMI in the forced swimming test, possibly by reducing an inhibitory function of beta 1-adrenoceptor mediated mechanisms.
本研究旨在阐明在大鼠强迫游泳试验中，与急性给药相比，去甲丙咪嗪（DMI）慢性治疗效果更佳是否是由于中枢β-肾上腺素能受体下调所致。重复给予DMI可激活大鼠行为模式，从而缩短不动时间。激活程度取决于治疗时长，即单次给药无效果，亚慢性给药（3次）有中度效果，慢性给药（31次）后有明显激活作用。DMI慢性治疗还导致大脑皮层中3H-二氢烯丙洛尔（3H-DHA）结合位点减少。脑室内（i.c.v.）注射异丙肾上腺素急性刺激脑β-肾上腺素能受体，虽只是部分地但显著减弱了慢性DMI通过β1-肾上腺素能受体相关机制产生的行为效应。同样，慢性i.c.v.联合给予β1-肾上腺素能受体拮抗剂阿替洛尔或普拉洛尔与DMI，可减弱慢性DMI引起的β-肾上腺素能受体下调及行为激活作用。另一方面，慢性i.c.v.给予异丙肾上腺素，推测会导致β-肾上腺素能受体下调，却增强了DMI的激活行为效应，单次给药就变得有效。然而，慢性给予异丙肾上腺素后，未观察到大脑皮层中3H-DHA结合参数的变化。这些结果表明，脑中β-肾上腺素能受体下调至少部分地导致了慢性DMI在强迫游泳试验中的显著激活效应，可能是通过减弱β1-肾上腺素能受体介导机制的抑制功能实现的。
