Somalwar Amita R, Choudhary Amit G, Sharma Pravesh R, B Nagalakshmi, Sagarkar Sneha, Sakharkar Amul J, Subhedar Nishikant K, Kokare Dadasaheb M
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, 440 033, India.
Department of Biotechnology, Savitribai Phule Pune University, Pune, 411 007, India.
Behav Brain Res. 2018 Aug 1;348:9-21. doi: 10.1016/j.bbr.2018.03.035. Epub 2018 Mar 23.
Although the role of cocaine- and amphetamine-regulated transcript peptide (CART) in modulating the mesolimbic reward pathway has been suggested, underlying cellular mechanisms have not been elucidated. Herein, we investigate the involvement of G dependent protein kinase A (PKA)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling in CART induced reward behavior. The rat was implanted with a stimulating electrode targeted at the lateral hypothalamus (LH)-medial forebrain bundle (MFB) and conditioned to intracranial self-stimulation (ICSS) in an operant chamber. Intracerebroventricular (icv) administration of CART (55-102) dose-dependently lowered ICSS threshold suggesting reward promoting action, however, pretreatment with subeffective doses of G inhibitor (pertussis toxin, PTX) or PKA inhibitor (Rp-cAMPS) or ERK inhibitor (U0126) via icv route, attenuated CART mediated reward experience. Operant conditioned rats showed increased pCREB levels in the nucleus accumbens shell (AcbSh), ventral tegmental area (VTA) and hypothalamic paraventricular nucleus (PVN). Infusion of CART (icv) in the conditioned rats augmented the population of pCREB positive cells in the AcbSh, VTA and PVN areas, but not in the arcuate nucleus (ARC). Pretreatment with U0126 significantly decreased CART induced pCREB activation in the AcbSh and VTA, but not in PVN and ARC. ICSS or CART induced CREB mRNA expression in Acb and VTA was attenuated by U0126. We suggest that recruitment of G dependent PKA/ERK/CREB phosphorylation signaling in Acb and VTA might play an important role in CART induced reward behavior.
尽管已有研究表明可卡因和苯丙胺调节转录肽（CART）在调节中脑边缘奖赏通路中发挥作用，但其潜在的细胞机制尚未阐明。在此，我们研究了G蛋白依赖性蛋白激酶A（PKA）/细胞外信号调节激酶（ERK）/环磷酸腺苷反应元件结合蛋白（CREB）信号通路在CART诱导的奖赏行为中的作用。将刺激电极植入大鼠下丘脑外侧区（LH）-内侧前脑束（MFB），并在操作性条件反射箱中对其进行颅内自我刺激（ICSS）训练。脑室内（icv）注射CART（55-102）剂量依赖性地降低了ICSS阈值，提示其具有奖赏促进作用，然而，通过icv途径预先给予亚有效剂量的G蛋白抑制剂（百日咳毒素，PTX）或PKA抑制剂（Rp-cAMPS）或ERK抑制剂（U0126），可减弱CART介导的奖赏体验。操作性条件反射大鼠伏隔核壳（AcbSh）、腹侧被盖区（VTA）和下丘脑室旁核（PVN）中的磷酸化CREB（pCREB）水平升高。在条件反射大鼠中icv注入CART可增加AcbSh、VTA和PVN区域中pCREB阳性细胞的数量，但在弓状核（ARC）中未增加。预先用U0126处理可显著降低CART诱导的AcbSh和VTA中pCREB的激活，但在PVN和ARC中未降低。U0126减弱了ICSS或CART诱导的Acb和VTA中CREB mRNA的表达。我们认为，Acb和VTA中G蛋白依赖性PKA/ERK/CREB磷酸化信号通路的激活可能在CART诱导的奖赏行为中起重要作用。
