Variations in Effects of Elevated Corticosterone Related to Drug Delivery Method: Plasma Concentration, Dentate Gyrus Neurogenesis, and Development of Trace Eyeblink Conditioning

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Exogenous glucocorticoids are commonly used in modern medications even though adverse effects on hippocampal-dependent learning and memory have been reported. Studies examining the effects of glucocorticoids on the developing brain and behavior report inconsistent results. Such studies require a reliable, long-term method of drug administration, and recent reports have questioned the reliability of available drug delivery methods in mice. In our laboratory, variable behavioral results using trace eyeblink conditioning (EBC) suggest that we may be having similar problems in developing rat pups.
To better understand this issue, we conducted a detailed time-course assessment of blood plasma concentrations of corticosterone (CORT) to compare 3 common methods of administration starting on postnatal day 15 in Long-Evans rat pups: s.c. pellet (35 mg, 21-day slow-release), s.c.injection (twice daily, 3 days, 20 mg/kg), and s.c. osmotic mini-pump (release rate 1μL/hr), with appropriate vehicle controls for each. For CORT plasma assays, blood samples were taken over the course of 7 days for pellets and over 3 days for injections and minipumps. Additionally, some of the animals in each group received three daily intraperitoneal injections of BrdU (50 mg/kg) on postnatal days 16-18, in order to study possible CORT effects on neurogenesis. Ten days after the last BrdU injection, brains were harvested. Coronal sections containing dorsal hippocampus were collected, immunostained and scanned with a confocal microscope. Stereological analysis focused on quantifying newly generated neurons using the Rare Events Protocol.
Trace EBC was impaired by pellets and minipumps but facilitated by injections. Pellets produced peak plasma CORT elevations up to 3800 ng/ml at 4 hours post-surgery and returned to baseline within 5 days. Injection produced a peak plasma elevation of CORT of up to 2000 ng/ml at 1 hour after each injection, which returned to baseline within 4 hours, producing a fluctuating pattern of elevations. Minipumps produced peak CORT elevation of 527 ng/ml 1 hour after surgery, which corresponded with surgical stress-related elevation in control animals. CORT elevation then dropped to a relatively steady level for the next 3 days at 200-300 ng/ml. These findings suggest that the different peak levels and elevation patterns of these three CORT delivery methods are likely to yield differences in behavioral outcomes. However, the total number of newly generated neurons in the days immediately following CORT administration, and their density in dorsal dentate gyrus, were not significantly influenced by the elevated CORT, regardless of delivery method.


Abstract from the 42nd Annual Meeting of the Society for Neuroscience, New Orleans, LA, October 13-17, 2012.