NEUROBIOLOGY OF REINFORCEMENT, CRAVING AND RELAPSE

反复暴露于滥用药物会产生特定的神经适应， 中脑边缘多巴胺系统，可以改变这两个主要和 药物的次级强化特性，并有助于复发 寻求毒品的行为。在神经核（NAc）中， 神经适应可能是由基因表达改变介导的， 药物诱导的转录因子CREB（cAMP反应）的变化 元件结合蛋白）和deltaFosB，Fos相关抗原（FRA） 慢性而非急性药物暴露所致。同样，重复用药 暴露产生GluR 1（AMPA谷氨酸受体）的上调 亚单位，在腹侧被盖区（VTA），和下调的 NAc中的GluR 2亚基。我们假设这些神经适应 有助于与药物相关的特定动机变化 成瘾，例如对强化的敏感或耐受 药物的性质，或提高药物的能力，压力， 与药物相关的（条件）刺激，以触发觅药复发 行为拟议中的研究将通过使用动物来验证这一假设 VTA中这些靶蛋白的遗传改变水平， NAc 1）通过用含有以下基因的病毒载体直接转染 在大鼠中的靶蛋白;和2）通过使用缺乏或过量的突变小鼠， 表达靶蛋白的基因。初步研究表明， 这些转基因动物对药物的反应发生了改变 其他药物相关行为的滥用（见行为核心）。的 项目4中的研究将通过测试以下因素的影响来扩展这些研究： 在直接行为测量上遗传调节靶蛋白， 药物的主要和次要强化特性，以及药物的复发， 由药物、条件刺激和压力引发的寻药行为。 对慢性药物暴露的一些神经适应类似于 神经退行性过程，并且可以通过输注或 神经营养因子进入腹侧被盖区或腹侧被盖区。而且一些 上述神经适应性可以通过这些因素来改变。 初步研究发现， 与毒品有关的行为。因为这些不同的神经适应 被假设为有助于与药物相关的动机变化 成瘾，拟议的研究将测试是否治疗与 神经营养因子可以改变原发性和继发性神经营养不良的直接行为指标， 二次毒品强化和觅药行为复发 由药物条件刺激和压力引发

Repeated exposure to drugs of abuse produces specific neuroadaptations in the mesolimbic dopamine system that could alter both the primary and secondary reinforcing properties of the drugs, and contribute to relapse of drug-seeking behavior. In the nucleus accumbens (NAc), some of these neuroadaptations could result from altered gene expression mediated by drug-induced changes in the transcription factors, CREB (cAMP-Response Element Binding protein) and deltaFosB, a Fos-related Antigen (FRA) induced by chronic, but not acute, drug exposure. Similarly, repeated drug exposure produce an up-regulation of GluR1, an AMPA glutamate receptor subunit, in the ventral tegmental area (VTA), and a down-regulation of the GluR2 subunit in the NAc. Our hypothesis is that these neuroadaptations contribute to specific motivational changes associated with drug addiction, for example with sensitization or tolerance to the reinforcing properties of the drugs, or to enhance the ability of drugs, stress, and drug-associated (conditioned) stimuli to trigger relapse of drug-seeking behavior. The proposed studies will test the hypothesis by using animals with genetically altered levels of these target proteins in the VTA and NAc 1) by direct transfection with a viral vector containing the gene for the target protein in rats; and 2) by using mutant mice that lack or over express the gene for the target protein. Preliminary studies demonstrate that these genetically modified animals exhibit altered responses to drugs of abuse in other drug-related behaviors (see Behavioral Core). The studies in Project 4 will extend these studies by testing the effects of genetically modulating the target protein on direct behavioral measures of the primary and secondary reinforcing properties of drugs, and relapse of drug-seeking behavior triggered by drugs, conditioned stimuli, and stress. Some neuroadaptations to chronic drug exposure resemble a neurodegenerative process, and can be prevented or reversed by infusion or neurotrophic factors into the VTA or NAc. Moreover, some of the neuroadaptations mentioned above can be modified by these factors. Preliminary studies have found highly potent actions of neurotrophic factors on drug-related behaviors. Since these various neuroadaptations are hypothesized to contribute to motivations changes associated with drug addiction, the proposed studies will test whether treatment with neurotrophic factors can alter direct behavioral measures of primary and secondary drug reinforcement, and relapse of drug-seeking behavior triggered by drugs, conditioned stimuli, and stress.