Inhibitory modulation of CART peptides in accumbal neuron through decreasing interaction of CaMKIIα with dopamine D3 receptors
Inhibitory modulation of CART peptides in accumbal neuron through decreasing interaction of CaMKIIα with dopamine D3 receptors
复制标题
DOI：
10.1016/j.brainres.2014.02.024
复制
发表时间：
2014-04-04
期刊：
影响因子：
2.9
通讯作者：
Hu, Zhenzhen
中科院分区：
文献类型：
--
作者：
Cai, Zhenyu;Zhang, Dalei;Hu, Zhenzhen
先前对大鼠的研究表明，将可卡因和安非他明调节转录物（CART）肽微量注射到延髓核（NAc;介导药物奖励和强化的大脑区域）中可以减弱精神兴奋剂的运动效应。CART肽还显示在海马神经元的原代培养物中诱导降低的细胞内钙（Ca 2+）浓度。本研究的目的是在原代培养的延髓神经元中表征Ca 2 +/钙调素依赖性激酶（CaMKIIa）与多巴胺D-3（D-3）受体（R）的相互作用。这种相互作用涉及CART肽的抑制性调节。在体外，CART（55-102）肽（0.1、0.5或1.44）可剂量依赖性地抑制K+去极化引起的海马神经元Ca ~（2+）内流和CaMKIIa磷酸化。此外，还发现CART肽阻断可卡因（1 μ M）诱导的Ca 2+内流、CaMKII α磷酸化、CaMKII α-D3 R相互作用和CREB磷酸化。在体内，重复微量注射CART（55-102）肽（2 μ g/1 μ l/侧）到NAc超过5天的时间内没有影响的行为活动，但阻断可卡因诱导的自发活动。这些结果表明，D3 R功能在海马神经元是CART（55-102）肽的靶点，并表明CART肽通过去磷酸化边缘D（3）R可能具有治疗可卡因滥用的潜力。(c)2014爱思唯尔有限公司版权所有。
Previous studies in rats have shown that microinjections of cocaine- and amphetamine-regulated transcript (CART) peptide into the nucleus accumbens (NAc; the area of the brain that mediates drug reward and reinforcement) attenuate the locomotor effects of psychostimulants. CART peptide has also been shown to induce decreased intracellular concentrations of calcium (Ca2+) in primary cultures of hippocampus neurons. The purpose of this study was to characterize the interaction of Ca2+/calmodulin-dependent kinases (CaMKIIa) with dopamine D-3 (D-3) receptors (R) in primary cultures of accumbal neurons. This interaction is involved in inhibitory modulation of CART peptides. In vitro, CART (55-102) peptide (0.1, 0.5 or 1 44) was found to dose-dependently inhibit K+ depolarization-elicited Ca2+ influx and CaMKIIa phosphorylation in accumbal neurons. Moreover, CART peptides were also found to block cocaine (1 mu M)-induced Ca2+ influx, CaMKII alpha phosphorylation, CaMKII alpha-D3R interaction, and CREB phosphorylation. In vivo, repeated microinjections of CART (55-102) peptide (2 mu g/1 mu l/side) into the NAc over a 5-day period had no effect on behavioral activity but blocked cocaine-induced locomotor activity. These results indicate that D3R function in accumbal neurons is a target of CART (55-102) peptide and suggest that CART peptide by dephosphorylating limbic D(3)Rs may have potential as a treatment for cocaine abuse. (c) 2014 Elsevier B.V. All rights reserved.