Adrenalectomy reverses chronic injection-induced tolerance to nicotine.

A recent study from our laboratory has demonstrated that C57BL/6 male mice that are chronically injected with nicotine develop a profound tolerance to nicotine that is not associated with changes in brain nicotinic receptors. We have proposed that alterations in the secretion of corticosterone (CCS) may regulate tolerance development in chronically injected animals. In the present study we have directly tested this hypothesis. Female DBA/2 mice were injected three times each day for 12 days with saline or 2 mg/kg nicotine. Blood samples were collected at various time points during the course of treatment and plasma CCS levels were determined. The animals were divided into two groups following the last injection on day 12. The first group of animals was tested for nicotine-induced release of corticosterone on day 13 of the experiment and then sacrificed. The brains of these animals were subsequently used to measure nicotinic receptor binding. The second group of animals was adrenalectomized (ADX) or sham-operated on day 13 of the experiment and tested for nicotine sensitivity on day 14 of the experiment. Plasma CCS levels were significantly elevated in animals that were chronically injected with nicotine (versus saline controls) by the fourth day of the experiment. Chronic nicotine-injected animals were tolerant to nicotine-induced CCS release. Animals that were chronically injected with nicotine and sham-operated were tolerant to acute nicotine challenge; however, tolerance to nicotine was not detected in ADX animals. These data support the hypothesis that the capacity to release CCS may underscore the expression of tolerance to nicotine in chronically injected animals.