Umathe S N, Bhutada P S, Jain N S, Shukla N R, Mundhada Y R, Dixit P V
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440 033, Maharashtra, India.
Neuropeptides. 2008 Aug;42(4):399-410. doi: 10.1016/j.npep.2008.04.005. Epub 2008 Jun 3.
Corticotrophin-releasing factor (CRF) is reported to inhibit the release of gonadotropin-releasing hormone (GnRH). In addition to the endocrine effects, GnRH is reported to influence the behavior via its neuronal interactions. We therefore, hypothesized that anxiety and depression produced by CRF could be also subsequent to the decrease in GnRH. To support such possibility, we investigated the influence of GnRH agonists on CRF or CRF antagonist induced changes in social interaction time in social interaction test, and immobility time in forced swim test in mice, as the indices for anxiety and depression, respectively. Results indicated that GnRH agonists [leuprolide (20-80 ng/mouse, i.c.v.), or d-Trp-6-LHRH (40-160 ng/mouse, i.c.v.)] dose dependently increased social interaction time and decreased immobility time indicating anxiolytic- and antidepressant-like effect, respectively. Such effects of GnRH agonists were even evident in castrated mice, which suggest that these effects were unrelated to their endocrine influence. Administration of CRF (0.1 and 0.3 nmol/mouse, i.c.v.) produced just opposite effects as that of GnRH agonist on these parameters. Further, it was seen that pretreatment with leuprolide (10 or 20 ng/mouse, i.c.v.) or d-Trp-6-LHRH (20 or 40 ng/mouse, i.c.v.) dose dependently antagonized the effects of CRF (0.3 nmol/mouse, i.c.v.) in social interaction and forced swim test. CRF antagonist [alpha-Helical CRF (9-41), (1 or 10 nmol/mouse, i.c.v.)] was found to exhibit anxiolytic- and antidepressant-like effect, and its sub-effective dose (0.1 nmol/mouse, i.c.v.) when administered along with sub-threshold dose of leuprolide (10 ng/mouse, i.c.v.), or d-Trp-6-LHRH (20 ng/mouse, i.c.v.) also produced significant anxiolytic- and antidepressant-like effect. These observations suggest reciprocating role of GnRH in modulating the CRF induced anxiogenic- and depressant-like effects.
据报道，促肾上腺皮质激素释放因子（CRF）可抑制促性腺激素释放激素（GnRH）的释放。除了内分泌作用外，据报道GnRH还通过其神经元相互作用影响行为。因此，我们推测CRF产生的焦虑和抑郁也可能继发于GnRH的减少。为了支持这种可能性，我们分别研究了GnRH激动剂对CRF或CRF拮抗剂诱导的小鼠社交互动测试中社交互动时间变化以及强迫游泳测试中不动时间变化的影响，将其作为焦虑和抑郁的指标。结果表明，GnRH激动剂[亮丙瑞林（20 - 80 ng/小鼠，脑室内注射）或d-Trp-6-LHRH（40 - 160 ng/小鼠，脑室内注射）]剂量依赖性地增加社交互动时间并减少不动时间，分别表明具有抗焦虑和抗抑郁样作用。GnRH激动剂的这种作用在去势小鼠中甚至更明显，这表明这些作用与其内分泌影响无关。脑室内注射CRF（0.1和0.3 nmol/小鼠）对这些参数产生的作用与GnRH激动剂相反。此外，还发现用亮丙瑞林（10或20 ng/小鼠，脑室内注射）或d-Trp-6-LHRH（20或40 ng/小鼠，脑室内注射）预处理剂量依赖性地拮抗了CRF（0.3 nmol/小鼠，脑室内注射）在社交互动和强迫游泳测试中的作用。发现CRF拮抗剂[α-螺旋CRF（9 - 41），（1或10 nmol/小鼠，脑室内注射）]表现出抗焦虑和抗抑郁样作用，当其亚有效剂量（0.1 nmol/小鼠，脑室内注射）与阈下剂量的亮丙瑞林（10 ng/小鼠，脑室内注射）或d-Trp-6-LHRH（20 ng/小鼠，脑室内注射）一起给药时，也产生了显著的抗焦虑和抗抑郁样作用。这些观察结果表明GnRH在调节CRF诱导的致焦虑和抑郁样作用中具有相互作用的作用。
