Peng Qinghua, Sun Xi, Liu Ziyong, Yang Jianghua, Oh Ki-Wan, Hu Zhenzhen
Department of Anesthesiology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 33006, China.
Evidence Identification Center, Department of Jiangxi Provincial Public Security, Nanchang, Jiangxi 33006, China.
Neurochem Int. 2014 Sep;75:105-11. doi: 10.1016/j.neuint.2014.06.005. Epub 2014 Jun 19.
Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5'-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55-102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55-102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55-102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55-102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55-102.
反复接触成瘾性药物会增强多巴胺受体（DR）信号传导，并最终增强伏隔核（NAcc）中环状单磷酸腺苷（cAMP）反应元件结合蛋白（CREB）调节的可卡因和苯丙胺调节转录物（CART）的磷酸化。已知这些效应有助于行为敏化的表达。CART肽是调节药物奖赏和强化的神经肽。本实验研究了向NAcc微量注射CART 55-102对（1）CREB的磷酸化、（2）cAMP/蛋白激酶A（PKA）信号传导和（3）细胞外信号调节激酶（ERK）磷酸化激酶信号传导的影响。在此，我们表明，向NAcc反复微量注射CART 55-102肽（1.0或2.5μg，每侧0.5μl）可减弱该部位可卡因诱导的D1R、D2R和D3R磷酸化增强。此外，在反复注射可卡因（15mg/kg）之前微量注射CART 55-102，在可卡因给药的第五天剂量依赖性地阻断了cAMP水平、PKA活性以及pERK和pCREB水平的增强。大鼠中可卡因诱导的运动活性和行为敏化也受到连续5天微量注射CART肽的抑制。这些结果表明，CART 55-102肽通过抑制D1R和D2R刺激、D3R磷酸化、cAMP/PKA信号传导和ERK磷酸化激酶信号传导，阻断了可卡因在NAcc中诱导的CREB磷酸化。这些效应可能在接受CART 55-102微量注射的大鼠行为敏化中发挥了代偿性抑制作用。
