Activating and Inhibitory PKA mutations in drug abuse

描述（由申请人提供）： 该提案将测试以下假设：激活PKA依赖性磷酸化的能力的急性和慢性变化是成瘾行为的基础，并且涉及产生两种结构，其将允许以细胞特异性和时间方式表达CRE重组酶。该重组酶将用于开启多巴胺D1或D2受体表达细胞中的激活和抑制性蛋白激酶A（PKA）突变，以研究激酶活性改变对药物寻求行为和复发的影响。我们假设，在D1受体表达细胞中激活PKA活性的突变将抑制自我给药和药物服用行为的复发，而在D2表达细胞中抑制PKA活性的突变将增强药物寻求行为并诱导复发。详细了解慢性药物暴露过程中特定脑区发生的分子变化，这些变化是随后行为变化的基础，可能为药理学干预提供新的治疗靶点。

DESCRIPTION (provided by applicant): This proposal will test the hypothesis that acute and chronic changes in the ability to activate PKA dependent phosphorylation underlie addictive behaviors and involves generating two constructs that will allow expression of CRE recombinase in a cell specific and temporal fashion. This recombinase will be used to turn on activating and inhibitory protein kinase A (PKA) mutations in dopamine D1 or D2 receptor expressing cells in order to investigate the effects of altered kinase activity on drug seeking behavior and relapse. We hypothesize that mutations that activate PKA activity in D1 receptor expressing cells will inhibit self-administration and relapse of drug taking behavior while mutations that inhibit PKA activity in D2 expressing cells will enhance drug seeking behavior and induce relapse. A detailed understanding of the molecular changes that occur in specific brain regions during chronic drug exposure that underlie the subsequent behavioral changes may provide novel therapeutic targets for pharmacological intervention.