The objective of this project is to gain insight into the mechanisms underlying the changes in expression of the beta-adrenergic receptors induced by various treatments. We have continued to probe the mechanisms of agonist and antagonist induced changes in beta-adrenergic receptor (beta-AR) mRNA levels in C6 glioma cells. In this, we have found that pretreatment with a microtubules disrupter can block agonist-induced down-regulation of beta1-AR mRNA while enhancing the down-regulation of beta 2-AR mRNA. The implied differences in the way the two beta-AR subtypes are regulated in C6 glioma cells were supported by experiments using protein synthesis inhibitor, cycloheximide. Thus, microtubule disrupting agents can be used as a tool for clarifying aspects of the changes induced by agonists and antagonists. We have extended our investigation of the interaction between serotoninergic and beta-adrenergic receptor systems at the level of mRNA expression and continue to find promising evidence that there is cross-regulation between serotonin receptors and beta-AR mRNA levels. We have also initiated a study of possible involvement on the peripheral benzodiazepine receptor in the action of carbamazepine to increase the expression of beta 2-AR mRNA and protein. The preliminary findings indicate that this induction might be mediated by mitochondrial neurosteroid biosynthesis. In view of the actions of a number of drugs used in the treatment of depression on the serotoninergic and beta-adrenergic receptor systems, we hope that a better understanding of the mechanisms regulating the expression of the beta-AR will offer insight into the nature and effective treatment of this mental disorder.
