Neural Mechanisms of Propensity for Drug Taking

 描述(申请人提供)：当提供食物或可卡因时，伏隔核(NAC)中的多巴胺(DA)最初发出信号，表明物品是有回报的。当行为，如吸毒，变得强迫性时，我们假设这反映了维持行为的神经系统的变化。背外侧纹状体(DLS)DA释放增强，NAc DA释放减弱。此外，在DLS中，从纹状体到黑质的直接通路中对启动食欲行为很重要的活动被增强，而从纹状体到苍白球的间接通路中抑制竞争性重复或刻板行为的活动被减弱。女性(女性和实验鼠)表现出比男性更快的吸毒升级，雌二醇(E2)增强了吸毒的获得性和滥用药物的动机。Becker实验室的实验已经证明，E2抑制DLS中GABA的释放，下调DA D2受体(D2DR)，并增强可卡因或安非他明刺激的DLS中DA的释放，但不增加NAC中的DA释放。这一建议的主要假设是：1)在DLS中，减弱可卡因诱导的NAC中DA的增加，并增强DA对可卡因的增加，与男性和女性对可卡因的偏好有关；2)雌二醇在女性DLS中的作用增强了可卡因诱导的多巴胺(DA)增加，抑制了GABA的释放，并抑制了D2 DA受体。这种综合作用提高了女性对可卡因的偏好形成和动机；3)DLS中间接途径的抑制减少有助于增强男性和女性对可卡因的动机。在女性中，D2DR在这一途径中被E2下调，这有助于女性更快地形成偏好，并比颗粒更有动力使用可卡因。确定(S)调节形成对可卡因的偏好而不是非常可口的食物奖励的机制，以及个体差异和性别差异如何对此做出贡献，对于我们理解和治疗男性和女性的成瘾都很重要。

 DESCRIPTION (provided by applicant): When presented with food or cocaine, dopamine (DA) in the nucleus accumbens (NAc) initially signals that the item is rewarding. When behaviors, such as drug taking, become compulsive we hypothesize that this reflects a shift in neural systems maintaining the behavior. There is enhanced DA release in the dorsolateral striatum (DLS) and attenuation of NAc DA release. Furthermore, within DLS, activity in the Direct Pathway from the striatum to the substantia nigra, that is important for initiation of appetitive behaviors is enhanced, while activity in the Indirect Pathway, from the striatum to the globus pallidus, that inhibits competing repetitive or stereotyped behaviors is attenuated. Females (women and laboratory rats) exhibit more rapid escalation of drug taking than do males and estradiol (E2) enhances acquisition of drug taking and motivation for drugs of abuse. Experiments from the Becker laboratory have demonstrated that E2 inhibits GABA release, down-regulates DA D2 receptors (D2DR), and enhances cocaine- or amphetamine-stimulated DA release in DLS but not NAc. The overarching hypotheses for this proposal are: 1) An attenuated cocaine-induced DA increase in NAc combined with an enhanced DA increase to cocaine in DLS is related to the propensity to develop a preference for cocaine over palatable food pellets in both males and females; 2) Estradiol's action in DLS of females enhances the cocaine-induced dopamine (DA) increase, inhibits GABA release, and inhibits D2 DA receptors. This combined effect enhances the rate of preference formation and motivation for cocaine over pellets in females; and 3) Decreased inhibition of the indirect pathway in DLS contributes to enhanced motivation for cocaine over pellets in both males and females. In females D2DRs are down-regulated in this pathway by E2, and this contributes to the more rapid preference formation in females and greater motivation for cocaine over pellets. Determining the mechanism(s) mediating formation of preference for cocaine over a highly palatable food reward, and how individual differences and sex differences contribute to this, are important for our understanding of and treatment of addiction in both men and women.