Activating and Inhibitory PKA mutations in drug abuse

描述(由申请人提供)： 这项提议将检验这一假设，即激活依赖于PKA的磷酸化能力的急性和慢性变化是成瘾行为的基础，并涉及产生两个结构，允许Cre重组酶以细胞特异性和时间性的方式表达。这种重组酶将被用来激活和抑制多巴胺D1或D2受体表达细胞中的蛋白激酶A(PKA)突变，以研究蛋白激酶A活性的变化对药物寻找行为和复发的影响。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身给药和吸毒行为的复发，而在D2受体表达细胞中抑制PKA活性的突变将增强药物寻找行为并诱导复发。对慢性药物暴露期间特定脑区发生的分子变化的详细了解，可能为药物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.