Ephrins and Repeated Cocaine

反复接触精神兴奋剂，如可卡因或安非他明，会导致大鼠运动能力和刻板行为的持续增强，这种现象被称为行为敏感化。有研究认为，行为敏化背后的神经元可塑性导致精神兴奋剂的激励效应增强，从而导致药物渴求。因此，对行为致敏机制的研究可以为中枢神经系统的可塑性提供新的见解，这可能有助于阐明人类精神兴奋剂成瘾者转向强迫性药物使用的机制。越来越多的证据表明，质膜结合的ephrin配体及其受体Eph酪氨酸激酶在发育和成熟神经系统的突触重塑中起着关键作用。最近，ephrin及其受体被证明影响中脑端多巴胺系统的可塑性，该系统介导了对精神兴奋剂行为敏感化的发展和长期表达。在哺乳动物中，迄今已鉴定出8种ephrinA1-ephrinA5； ephrinB1-ephrinB3)和13种Eph受体（EphA1-EphA8; EphB1-EphB4, EphB6）。本拨款申请的目的是评估急性和反复注射可卡因对新纹状体、伏隔核核和壳、黑质和/或腹侧端区EphB1和ephrin-B2表达的影响。我们还将评估反义寡核苷酸抑制这些细胞核中EphB1受体表达对可卡因行为致敏发展的影响。所有这些实验都将使用大鼠作为实验对象。

Repeated exposure to psychostimulants, such as cocaine or amphetamine, leads to a progressive and enduring augmentation of locomotor and stereotyped behaviors in rats, a phenomenon known as behavioral sensitization. It has been suggested that the neuronal plasticity underlying behavioral sensitization results in the enhancement of the incentive motivational effects of psychostimulants, which contributes to drug craving. Thus, studies examining the mechanisms underlying behavioral sensitization could provide new insight into plasticity in the central nervous system that may help elucidate the mechanisms underlying the shift to compulsive drug use among human psychostimulant addicts. Growing evidence indicates that the plasma membrane-bound ephrin ligands and their receptors, the Eph tyrosine kinases, play critical roles in synaptic remodeling both during development and in the mature nervous system. Recently, ephrins and their receptors were shown to influence plasticity in the mesotelencephalic dopamine systems, which mediate both the development and long-term expression of behavioral sensitization to psychostimulants. In mammals, eight ephrins (ephrinA1-ephrinA5; ephrinB1-ephrinB3) and thirteen Eph receptors (EphA1-EphA8; EphB1-EphB4, EphB6) have been identified to date. The goal of this grant application is to assess the influence of acute and repeated injections of cocaine on the expression of EphB1 and ephrin-B2 in the neostriatum, core and shell of the nucleus accumbens, substantia nigra and/or ventral termental area. We also will assess the influence of antisense oligonucleotide suppression of EphB1 receptor expression in these nuclei on the development of behavioral sensitization to cocaine. Rats will be used as subjects in all of these experiments.