Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland.
Neuroscience. 2010 Mar 10;166(1):122-31. doi: 10.1016/j.neuroscience.2009.12.015. Epub 2009 Dec 17.
The present study investigated the involvement of 5-HT(1A) receptors in the inhibitory effect of single administration of cocaine (COC, 15 mg/kg i.p.) on the induction of long-term potentiation (LTP) in slices of rat dentate gyrus (DG), prepared 30 min and 2 days after COC administration. These effects of COC were blocked by an antagonist of 5-HT(1A) receptors, WAY 100635 (0.4 mg/kg i.p.), which had been administered 20 min before COC. The detrimental effect of COC on LTP in slices prepared 30 min after COC administration could be prevented by blocking glucocorticoid receptors (GRs) using mifepristone (RU 38486, 10 mg/kg s.c. given 1 h before COC), similar as in slices obtained 2 days after COC as reported previously [Maćkowiak et al. (2008) Eur J Neurosci 27:2928-2937]. After a single administration of an agonist of 5-HT(1A) receptors, 8-OH-DPAT, (0.5 mg/kg i.p.), the level of LTP in slices prepared 2 days later was significantly decreased resembling the effect of COC. This effect of 8-OH-DPAT was antagonized by WAY 100635 (0.4 mg/kg i.p.), administered 20 min before 8-OH-DPAT and by RU 38486, given 1 h before 8-OH-DPAT. COC-induced inhibition of LTP could be blocked by the inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), SL 327 (50 mg/kg i.p.), administered 1 h before COC, but not by the inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), LY 294002 (80 mg/kg i.p.). COC-induced reduction in the number of polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neurons in rat dentate gyrus could also be prevented by WAY 100635, given 20 min before COC. These data indicate that the indirect 5-HT(1A) receptor activation by a single COC administration and subsequent stimulation of extracellular signal-regulated kinases (ERK 1/2) signaling pathway result in a decrease of the potential for long-term increase in synaptic efficacy in rat DG lasting at least two but less than 7 days, most likely via activation of the hypothalamic-pituitary-adrenal (HPA) axis.
本研究探讨了 5-HT（1A）受体在单次给予可卡因（COC，15mg/kg 腹腔注射）抑制大鼠齿状回（DG）切片长时程增强（LTP）诱导中的作用。COC 的这些作用被 5-HT（1A）受体拮抗剂 WAY 100635（0.4mg/kg 腹腔注射）阻断，WAY 100635 在 COC 给药前 20 分钟给药。COC 给药 30 分钟后，COC 对 LTP 的有害影响可以通过阻断糖皮质激素受体（GRs）来预防，使用 RU 38486（COC 前 1 小时给予 10mg/kg 皮下注射），与先前报道的 COC 给药 2 天后获得的切片相似[Maćkowiak 等人，（2008）Eur J Neurosci 27：2928-2937]。单次给予 5-HT（1A）受体激动剂 8-OH-DPAT（0.5mg/kg 腹腔注射）后，2 天后制备的切片中 LTP 的水平显著降低，类似于 COC 的作用。8-OH-DPAT 的这种作用被 WAY 100635（0.4mg/kg 腹腔注射）阻断，WAY 100635 在 8-OH-DPAT 前 20 分钟给药，也被 RU 38486 阻断，RU 38486 在 8-OH-DPAT 前 1 小时给药。COC 诱导的 LTP 抑制可被丝裂原激活蛋白激酶激酶 1/2（MEK1/2）抑制剂 SL 327（50mg/kg 腹腔注射）阻断，SL 327 在 COC 前 1 小时给药，但不能被磷脂酰肌醇 3-激酶（PI3-kinase）抑制剂 LY 294002（80mg/kg 腹腔注射）阻断。COC 诱导的大鼠齿状回中多唾液酸化神经细胞粘附分子（PSA-NCAM）阳性神经元数量减少也可被 WAY 100635 阻断，WAY 100635 在 COC 前 20 分钟给药。这些数据表明，单次 COC 给药引起的间接 5-HT（1A）受体激活，随后刺激细胞外信号调节激酶（ERK 1/2）信号通路，导致大鼠 DG 中突触效能长期增加的潜力降低，至少持续 2 天，但不超过 7 天，很可能是通过激活下丘脑-垂体-肾上腺（HPA）轴。
