Serra M, Concas A, Mostallino M C, Chessa M F, Stomati M, Petraglia F, Genazzani A R, Biggio G
Department of Experimental Biology, Chair of Pharmacology, University of Cagliari, Italy.
Psychoneuroendocrinology. 1999 Apr;24(3):269-84. doi: 10.1016/s0306-4530(98)00049-3.
Pivagabine [4-(2.2-dimethyl-l-oxopropylamino) butanoic acid] (PVG) is a hydrophobic 4-aminobutyric acid derivative with neuromodulatory activity. The effects of subchronic treatment with PVG on stress-induced changes both on brain concentrations of corticotropin-releasing factor (CRF) and neurosteroids and on the function of the gamma-aminobutyric acid type A (GABAA) receptor complex were investigated in male rats. Subchronic treatment with PVG (100-200 mg/kg, i.p.) resulted in a dose-dependent inhibition of the foot shock-induced increase in the binding of t-[35S]butylbicyclophosphorothionate to unwashed membranes prepared from the cerebral cortex of rats killed immediately after stress; PVG treatment alone had no effect on this parameter. This antagonistic action of PVG was also shown in adrenalectomized-orchietomized rats. Foot-shock stress decreased by 74% and increased by 125% the CRF concentration in the hypothalamus and cerebral cortex, respectively. PVG prevented these effects of stress on CRF concentration in both brain regions; this drug per se reduced hypothalamic CRF concentration by 52% but had no effect in the cortex. Moreover, intracerebroventricular injection of CRF, like stress, induced a dose-dependent increase of [35S]TBPS binding to cerebral cortical membranes: an effect not prevented by subchronic treatment of PVG. Finally, PVG did not antagonize the stress-induced increases in the concentrations of neuroactive steroids in brain or plasma. These results suggest that the marked antistress action of PVG is mediated by antagonizing the effects of stress on GABA(A) receptor function and CRF concentrations in the brain, but not by altering the stress-induced increase in neurosteroid concentrations.
匹伐加滨4-(2,2-二甲基-1-氧代丙基氨基)丁酸是一种具有神经调节活性的疏水性γ-氨基丁酸衍生物。在雄性大鼠中研究了PVG亚慢性治疗对应激诱导的促肾上腺皮质激素释放因子(CRF)和神经甾体脑浓度变化以及γ-氨基丁酸A型(GABAA)受体复合物功能的影响。PVG(100 - 200mg/kg，腹腔注射)亚慢性治疗导致剂量依赖性抑制足部电击诱导的t-[35S]丁基双环磷硫代酸盐与应激后立即处死的大鼠大脑皮质制备的未洗涤膜结合增加；单独的PVG治疗对该参数没有影响。PVG的这种拮抗作用在肾上腺切除-睾丸切除大鼠中也有显示。足部电击应激分别使下丘脑和大脑皮质中的CRF浓度降低74%和升高125%。PVG可预防应激对这两个脑区CRF浓度的这些影响；该药物本身使下丘脑CRF浓度降低52%，但对皮质没有影响。此外，脑室内注射CRF，与应激一样，诱导[35S]TBPS与大脑皮质膜结合的剂量依赖性增加：PVG亚慢性治疗不能预防这种作用。最后，PVG不能拮抗应激诱导的脑或血浆中神经活性甾体浓度的增加。这些结果表明，PVG显著的抗应激作用是通过拮抗应激对大脑中GABA(A)受体功能和CRF浓度的影响来介导的，而不是通过改变应激诱导的神经甾体浓度增加来实现的。
