Ephrins and Repeated Cocaine

反复暴露于精神兴奋剂，如可卡因或安非他明，导致大鼠的运动和刻板行为进行性和持久性增强，这种现象被称为行为敏化。已有研究表明，行为敏感化背后的神经元可塑性导致精神兴奋剂的激励动机效应增强，从而导致药物渴求。因此，研究行为敏化的潜在机制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潜在机制。越来越多的证据表明，质膜结合的肝配蛋白配体和它们的受体，Eph酪氨酸激酶，在发育和成熟的神经系统中的突触重塑中发挥关键作用。最近，肝配蛋白及其受体被证明会影响中脑多巴胺系统的可塑性，该系统介导对精神兴奋剂的行为敏化的发展和长期表达。在哺乳动物中，迄今已鉴定出8种ephrin（ephrinA 1-ephrinA 5; ephrinB 1-ephrinB 3）和13种Eph受体（EphA 1-EphA 8; EphB 1-EphB 4，EphB 6）。这项资助申请的目的是评估急性和重复注射可卡因对EphB 1和ephrin-B2在新纹状体、核壳、黑质和/或腹侧端区的表达的影响。我们还将评估反义寡核苷酸抑制EphB 1受体表达在这些细胞核中对可卡因的行为敏化的发展的影响。大鼠将用作所有这些实验的受试者。

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.