Regulation of Addictive Behavior by Dopamine Signaling

多巴胺信号传导对成瘾行为的调节

• 批准号: 6891869
• 负责人: David W Self
• 金额: $ 27.3万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891869
• 关键词: AMPA receptors; behavior test; behavioral /social science research tag; biological signal transduction; cocaine; craving; cyclic AMP; dopamine; dopamine receptor; drug addiction; genetically modified animals; laboratory mouse; laboratory rat; microwave radiation; neuroregulation; nucleus accumbens; phosphoproteins; phosphorylation; protein kinase A; receptor expression; receptor sensitivity; relapse /recurrence; self medication; substance abuse related behavior; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): The transition from drug use to an addicted state is signaled by marked escalation in drug intake and increased drug seeking during withdrawal. Our studies suggest that up-regulation in cAMP/PKA signaling pathways in nucleus accumbens (NAc) following chronic drug use directly contributes to this transition, possibly by differentially altering D1 and D2 receptor-mediated responses that regulate drug-taking and -seeking behaviors. To investigate this hypothesis, studies measure Dl and D2 receptor responsiveness before, during and after chronic cocaine self-administration in Low and High intake rats. Behavioral studies track sensitivity to Dl and D2 regulation of locomotion (unconditioned responses) and relapse to cocaine seeking (conditioned responses) in relation to both time and individual propensity for escalation. Parallel biochemical studies track changes in downstream cAMP-dependent protein phosphorylation and related signaling proteins before, during and after chronic cocaine self-administration, for comparison in Low and High intake rats and their yoked partners. The functional consequence of up-regulation in cAMP/PKA signaling is studied in three anatomically distinct models of cAMP/PKA up-regulation. The first model utilizes cholera toxin microinfusion in NAc core and shell subregions in rats. The other two models utilize inducible transgenic mice that over-express Gs proteins in either Dl/dynorphin- or D2/enkephalin-containing striatal neurons. These studies will test the relative contribution of cAMP/PKA up-regulation in distinct NAc subregions and specific striatal cell types to escalating cocaine intake, long-term relapse to cocaine seeking induced by drugs, cues, and stress. Studies also investigate the role of cAMP/PKA up-regulation on altered D 1 and D2 receptor responsiveness in locomotion and relapse, with downstream cAMP-dependent protein phosphorylation as a biochemical correlate. AMPA glutamate receptors in NAc may regulate addictive behavior via specific interactions with D1- and D2- regulated cAMP/PKA signaling pathways. These interactions are studied using viral-mediated over-expression of GluRl and GluR2 AMPA subunits in NAc neurons in assays of cocaine self-administration and relapse to cocaine seeking. Studies also test specific AMPA receptor interactions with D1 and D2 receptors in regulation of locomotion and relapse, and their dependence on cAMP/PKA signaling using a PKA insensitive GluR1 vector. Together, these studies combine relevant behavioral models with modem molecular techniques to investigate discrete neural and behavioral alterations that contribute to the addiction process

描述（由申请人提供）：从药物使用到成瘾状态的转变是通过药物摄入量的显著增加和戒断期间寻求药物的增加来发出信号的。我们的研究表明，在慢性药物使用后，cAMP/PKA信号通路在丘脑核（NAc）中的上调直接促成了这种转变，可能是通过差异改变D1和D2受体介导的反应，调节药物服用和寻求行为。为了研究这一假设，研究在低和高摄入大鼠中在慢性可卡因自我施用之前、期间和之后测量D1和D2受体反应性。行为研究追踪与时间和个体升级倾向两者相关的对D1和D2运动调节的敏感性（非条件反应）和对可卡因寻求的复发（条件反应）。平行的生化研究跟踪下游cAMP依赖性蛋白磷酸化和相关信号蛋白在慢性可卡因自我给药之前、期间和之后的变化，以在低和高摄入大鼠及其配对伴侣中进行比较。在cAMP/PKA上调的三个解剖学上不同的模型中研究了cAMP/PKA信号上调的功能后果。第一个模型利用霍乱毒素微输注在大鼠的NAc核心和壳亚区。另外两个模型利用可诱导的转基因小鼠，这些小鼠在含有D1/强啡肽或D2/脑啡肽的纹状体神经元中过表达Gs蛋白。这些研究将测试cAMP/PKA在不同NAc亚区和特定纹状体细胞类型中上调对可卡因摄入量增加、药物、线索和压力诱导的可卡因寻求长期复发的相对贡献。研究还调查了cAMP/PKA上调对运动和复发中改变的D1和D2受体反应性的作用，下游cAMP依赖性蛋白磷酸化作为生化相关性。NAc中AMPA谷氨酸受体可能通过与D1和D2调节的cAMP/PKA信号通路特异性相互作用来调节成瘾行为。在可卡因自我施用和可卡因寻求复发的测定中，使用NAc神经元中GluRl和GluR 2AMPA亚基的病毒介导的过表达来研究这些相互作用。研究还测试了特定AMPA受体与D1和D2受体在调节运动和复发中的相互作用，以及它们对cAMP/PKA信号传导的依赖性，使用PKA不敏感的GluR 1载体。总之，这些研究将联合收割机相关的行为模型与现代分子技术相结合，以研究有助于成瘾过程的离散神经和行为改变