Zhang Han-Ting, Whisler Lisa R, Huang Ying, Xiang Yang, O'Donnell James M
Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506-9137, USA.
Neuropsychopharmacology. 2009 Mar;34(4):1067-77. doi: 10.1038/npp.2008.184. Epub 2008 Oct 15.
The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including alpha-1, alpha-2, beta-1, and beta-2 subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the alpha-2 adrenergic antagonist idazoxan (0.1-2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5-2.5 mg/kg, i.p.) or centrally (1-10 microg, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the beta-adrenergic antagonists propranolol and CGP-12177 or the alpha-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of beta-adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in beta-1, beta-2, or both beta-1 and beta-2 adrenergic receptors. In addition, desipramine (3-30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both beta-1 and beta-2 adrenergic receptors. As antagonism of presynaptic alpha-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic alpha-2 adrenergic receptors play an important role in its antidepressant effects.
抗抑郁药地昔帕明抑制去甲肾上腺素（NE）的再摄取，导致突触前和突触后肾上腺素能受体激活，包括α-1、α-2、β-1和β-2亚型。然而，尚不清楚哪些肾上腺素能受体参与介导其抗抑郁作用。用地昔帕明（20mg/kg，腹腔注射）处理小鼠产生了抗抑郁样效应，强迫游泳试验中不动时间减少证明了这一点；这被α-2肾上腺素能拮抗剂伊达唑啉（0.1 - 2.5mg/kg，腹腔注射）预处理所拮抗。同样，外周给予（0.5 - 2.5mg/kg，腹腔注射）或中枢给予（1 - 10μg，脑室内注射）伊达唑啉，拮抗了地昔帕明在低速率差异强化（DRL）72秒程序下对大鼠产生的抗抑郁样效应，即反应率降低和强化率增加。相比之下，用β-肾上腺素能拮抗剂普萘洛尔和CGP - 12177或α-1肾上腺素能拮抗剂哌唑嗪预处理并没有改变地昔帕明对DRL行为的抗抑郁样效应。使用基因敲除品系证实了β-肾上腺素能受体不参与介导地昔帕明的行为效应。在强迫游泳试验中，缺乏β-1、β-2或同时缺乏β-1和β-2肾上腺素能受体的小鼠，地昔帕明诱导的不动时间减少没有改变。此外，地昔帕明（3 - 30mg/kg）对同时缺乏β-1和β-2肾上腺素能受体的小鼠在DRL 36秒程序下的行为产生了抗抑郁样效应。由于突触前α-2肾上腺素能受体的拮抗促进NE释放，增强了地昔帕明的作用，目前的结果表明突触后α-2肾上腺素能受体在其抗抑郁作用中起重要作用。
