Cai Zhenyu, Zhang Dalei, Ying Ying, Yan Min, Yang Jianhua, Xu Fangyun, Oh Kiwan, Hu Zhenzhen
Department of Pathophysiology, Medical College of Nanchang University, Nanchang 330006, China.
Department of Physiology, Medical College of Nanchang Universidy, Nanchang 330006, China.
Brain Res. 2014 Apr 4;1557:101-10. doi: 10.1016/j.brainres.2014.02.024. Epub 2014 Feb 20.
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 (Ca(2+)) in primary cultures of hippocampus neurons. The purpose of this study was to characterize the interaction of Ca(2+)/calmodulin-dependent kinases (CaMKIIα) with dopamine D3 (D3) 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 1μM) was found to dose-dependently inhibit K(+) depolarization-elicited Ca(2+) influx and CaMKIIα phosphorylation in accumbal neurons. Moreover, CART peptides were also found to block cocaine (1μM)-induced Ca(2+) influx, CaMKIIα phosphorylation, CaMKIIα-D3R interaction, and CREB phosphorylation. In vivo, repeated microinjections of CART (55-102) peptide (2μg/1μl/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 D3Rs may have potential as a treatment for cocaine abuse.
先前对大鼠的研究表明，向伏隔核（大脑中调节药物奖赏和强化作用的区域）微量注射可卡因和苯丙胺调节转录肽（CART）可减弱精神兴奋剂对运动的影响。CART肽还被证明可降低海马神经元原代培养物中细胞内的钙（Ca(2+)）浓度。本研究的目的是在伏隔核神经元原代培养物中表征钙/钙调蛋白依赖性激酶（CaMKIIα）与多巴胺D3（D3）受体（R）之间的相互作用。这种相互作用参与了CART肽的抑制性调节。在体外，发现CART（55-102）肽（0.1、0.5或1μM）可剂量依赖性地抑制伏隔核神经元中钾（K(+)）去极化引发的钙（Ca(2+)）内流和CaMKIIα磷酸化。此外，还发现CART肽可阻断可卡因（1μM）诱导的钙（Ca(2+)）内流、CaMKIIα磷酸化、CaMKIIα-D3R相互作用以及CREB磷酸化。在体内，在5天的时间里向伏隔核重复微量注射CART（55-102）肽（2μg/1μl/侧）对行为活动没有影响，但可阻断可卡因诱导的运动活动。这些结果表明，伏隔核神经元中的D3R功能是CART（55-102）肽的作用靶点，并表明CART肽通过使边缘系统的D3R去磷酸化可能具有作为可卡因滥用治疗方法的潜力。
