Measurement and Regulation of Central Noradrenergic Receptors

Abstract

Abstract : As proposed in the original application, research this year has concerned studies of the central noradrenergic neuronal system in reactions to stress. We have focused on the role of the noradrenergic system in long-term changes in brain function produced by stress. In previous work we had shown that activation of the noradrenergic system by the sympathomietic drug, yohimbine (YOH), or by stress increases the mRNA levels of the immediate early gene (IEG), c-fos. IEGs serve to regulate the transcription of other genes and may mediate long-term structural and functional changes in the brain during stress. In work done this year, we have shown that lesions of central noradrenergic neurons block the effects of YOH and stress on c-fos. This confirms the importance of norepinephrine (NE) release in the mediation of the central c-fos response. We have also shown that YOH can activate the gene for nerve growth factor (NGF) in the brain. NGF is a neurotrophic agent and may mediate the long-term structural and functional changes produced by noradrenergic activity during stress. With regard to the nature of these long-term effects we have shown that the noradrenergic system has protective actions on neurons in the substantial nigra during the administration of a neurotoxin. Thus protection of neurons from damage may be one of the long-term functions of the noradrenergic system during stress. In addition to these functional studies, we have also made progress on methological problems associated with the measurement of noradrenergic neurotransmission in vivo. We have found that an increase in beta adrenoreceptor activation during stress can be detected from measurement of extra cellular levels of cyclic AMP by micro dialysis. These findings may facilitate future studies of noradrenergic function in vivo during stress.