Stress and 5-HT1B autoreceptors in models of anxiety

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Serotonin (5-HT)1B autoreceptors are localized in the axon terminals of serotonergic neurons and provide feedback inhibition of serotonin synthesis and release. However, 5-HT1B receptors are expressed in many neuron types, making pharmacological analysis nearly unable to discern which populations produce a particular behavioral or physiological effect. This has led to confusion about their role in depressive and anxiety symptoms associated with impaired serotonergic neurotransmission. Most 5-HT fibers projecting to regions involved in these functions arise from the dorsal (DRN) or median (MRN) raphe nuclei, but there is considerable uncertainty as to how 5-HT release from these nuclei is controlled in disease states. We have been using viral gene transfer to examine the effects of DRN 5-HT1B over-expression on stress-sensitivity in two anxiety-related behaviors - open field test (OFT) and elevated-plus maze (EPM). In agreement with previous results showing increased DRN 5-HT1B expression in learned helpless rats, we found 5-HT1B overexpression in DRM increases anxiety behaviors. I propose to extend these studies to examine effects of 5-HT1B overexpression in the MRN, where I anticipate increased magnitude of EPM effects due to the involvement of MRN in benzodiazepine actions in this assay. To further establish the role of increased 5-HT1B autoreceptor expression in these effects, I will determine if SB-224289, a 5-HT1B antagonist reverses them. Finally. I will examine the effects of a key modulator of stress, corticotropin releasing factor (CRF), on 5-HT1B expression in the DRN. Since DRN and amygdala are reciprocally connected via 5-HT and CRF, investigating the functional relationship between CRF and 5-HT1B autoreceptors may help explain the interactions that these brain regions have in fear and anxiety behaviors. CRF has complex effects on 5-HT release from DRN projections, perhaps because both CRF receptors (R1 and R2) are expressed in DRN. CRF-R1 appears to inhibit 5-HT release, while CRF-R2 is excitatory. We propose to investigate the effect of subchronic infusion of selective CRF agonists into DRN on 5-HT1B mRNA regulation and anxiety behaviors. Chronic R1 activation should accordingly decrease 5-HT1B expression in DRN while increasing anxiety related behavior, while chronic R2 activation should produce the opposite effects.