Regulation of β1‐Adrenergic Receptor mRNA and Ligand Binding by Antidepressant Treatments and Norepinephrine Depletion in Rat Frontal Cortex

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Abstract
The number of β1-adrenergic receptor (β1AR) 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 β1AR binding sites in cerebral cortex. The present study was carried out to examine the influence of these treatments on levels of β1 AR mRNA in frontal cortex to study the molecular mechanisms that underlie the regulation of β1 ARs in brain. Levels of β1 AR mRNA were measured by RNase protection analysis using a riboprobe derived from rat β1AR cDNA, and the levels of βAR binding were measured using the nonselective ligand [3H]CGP-12177. Studies to verify the specificity of the RNase protection assay revealed that the distribution of β1AR mRNA was in agreement with the reported distribution of β1AR ligand binding: Levels of β1AR 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 βAR ligand binding and resulted in a corresponding, time-dependent down-regulation of β1AR mRNA levels in frontal cortex. However, imipramine administration regulated levels of β1AR mRNA in a biphasic manner, with treatments for 7–14 days increasing and treatments for 18–21 days decreasing levels of β1AR mRNA in frontal cortex. In contrast, levels of [3H]CGP-12177 ligand binding were decreased at all time points examined (3–21 days). The influence of NE depletion, using the neurotoxin 6-hydroxy-dopamine (6-OHDA), on levels of β1AR mRNA was also examined. Three days after 6-OHDA treatment, levels of [3H]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 β1AR mRNA were significantly decreased, and 14 days after treatment, levels of β1AR mRNA returned to control values. The results demonstrate that β1AR 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.