Adrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner

The objective of the present study was to investigate the contribution of adrenal stress hormones to strain differences in cocaine sensitivity. For this purpose, we have studied sensitisation to the locomotor stimulant effect of cocaine and, in parallel, cocaine-induced corticosterone secretion in two inbred mouse strains: C57BL/6 and DBA/2. Adrenalectomy (‘ADX’: surgical removal of the adrenal glands) was performed in a subset of animals to investigate the contribution of the adrenals. ADX and SHAM operated mice were subjected to repeated injections of cocaine (15.0 mg/kg) or saline for nine consecutive days, followed by a 5-day withdrawal interval and a saline challenge on day 14. All animals were challenged with 7.5 mg/kg cocaine on day 15. We report that repeated cocaine exposure induced locomotor sensitisation in both strains, while endocrine sensitisation was only observed in the DBA/2 strain. By contrast, cocaine attenuated corticosterone responses in C57BL/6 mice throughout the sensitisation paradigm. We have therefore identified one strain, the DBA/2 strain, that displays parallel sensitisation of cocaine-induced locomotion and -corticosterone secretion. Most interestingly, ADX prevented locomotor sensitisation only in DBA/2 mice, suggesting that behavioural sensitisation depends on the integrity of adrenal function and on secretion of adrenal glucocorticoids in this strain. The present results demonstrate that adrenal stress hormones facilitate behavioural sensitisation to cocaine in a genotype-dependent manner and suggest that glucocorticoids contribute to strain differences in psychostimulant sensitivity.