REGULATION OF BETA-1-ADRENERGIC RECEPTOR MESSENGER-RNA AND LIGAND-BINDING BY ANTIDEPRESSANT TREATMENTS AND NOREPINEPHRINE DEPLETION IN RAT FRONTAL-CORTEX

The number of beta1-adrenergic receptor (beta1AR) binding sites is decreased by chronic antidepressant treatments, including electroconvulsive seizure (ECS) and imipramine, whereas administration of agents that deplete norepinephrine (NE) increases the number of beta1AR binding sites in cerebral cortex. The present study was carried out to examine the influence of these treatments on levels of beta1AR mRNA in frontal cortex to study the molecular mechanisms that underlie the regulation of beta1ARs in brain. Levels of beta1AR mRNA were measured by RNase protection analysis using a riboprobe derived from rat beta1AR cDNA, and the levels of betaAR binding were measured using the nonselective ligand [H-3]CGP-12177. Studies to verify the specificity of the RNase protection assay revealed that the distribution of beta1AR mRNA was in agreement with the reported distribution of beta1AR ligand binding: Levels of beta1AR mRNA were highest in cerebral cortex or frontal cortex, intermediate in neostriatum, hippocampus, lung, and heart, and lowest in cerebellum, kidney, and liver. Chronic ECS treatment (once daily for 10 days) significantly decreased levels of betaAR ligand binding and resulted in a corresponding, time-dependent down-regulation of beta1AR mRNA levels in frontal cortex. However, imipramine administration regulated levels of beta1AR mRNA in a biphasic manner, with treatments for 7-14 days increasing and treatments for 18-21 days decreasing levels of beta1AR mRNA in frontal cortex. In contrast, levels of [H-3]CGP-12177 ligand binding were decreased at all time points examined (3-21 days). The influence of NE depletion, using the neurotoxin 6-hydroxydopamine (6-OHDA), on levels of beta1AR mRNA was also examined. Three days after 6-OHDA treatment, levels of [H-3]CGP-12177 ligand binding were not altered, but 7-14 days after neurotoxin treatment, levels of ligand binding were significantly increased. In contrast, 3-9 days after 6-OHDA treatment, levels of beta1AR mRNA were significantly decreased, and 14 days after treatment, levels of beta1AR mRNA returned to control values. The results demonstrate that beta1AR mRNA and ligand binding are regulated in parallel by ECS treatment but that levels of receptor mRNA are regulated in a complex manner by imipramine or 6-OHDA treatments, not predicted by changes in ligand binding.