Neural Mechanisms of Propensity for Drug Taking

 描述（由申请人提供）：当呈现食物或可卡因时，中脑核（NAc）中的多巴胺（DA）最初发出信号，表明该物品是奖励的。当行为，如吸毒，成为强迫性的，我们假设这反映了神经系统的转变，维持行为。背外侧纹状体（DLS）DA释放增强，NAc DA释放减弱。此外，在DLS内，从纹状体到黑质的直接途径中的活性（其对于食欲行为的起始是重要的）增强，而从纹状体到苍白球的间接途径中的活性（其抑制竞争性重复或刻板行为）减弱。女性（女性和实验室大鼠）表现出更快的药物服用的升级比男性和雌二醇（E2）增强收购的药物服用和滥用药物的动机。Becker实验室的实验表明，E2抑制GABA释放，下调DA D2受体（D2 DR），并增强可卡因或安非他明刺激的DA释放在DLS，但不NAc。该提议的首要假设是：1）可卡因诱导的NAc中DA增加减弱，与DLS中可卡因的DA增加增强相结合，与男性和女性对可卡因的偏好超过可口的食物颗粒的倾向有关; 2）Eklant在女性DLS中的作用增强可卡因诱导的多巴胺（DA）增加，抑制GABA释放，并抑制D2 DA受体。这种组合效应增强了女性对可卡因的偏好形成率和动机; 3）DLS中间接途径的抑制降低有助于增强男性和女性对可卡因的动机。在女性中，D2 DR在该途径中被E2下调，这有助于女性更快地形成偏好，并对可卡因产生更大的动机。确定机制（S）调解形成的偏好可卡因在一个非常可口的食物奖励，以及如何个人差异和性别差异有助于这一点，对于我们的理解和治疗成瘾的男性和女性是很重要的。

 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.