Stressor- or drug-induced sensitization of the corticosterone response is not critically involved in the long-term expression of behavioural sensitization to amphetamine.

Repeated exposure to drugs of abuse induces long-lasting behavioural sensitization, which is thought to play a role in the persistence of drug-seeking behaviour. Recently, we showed that repeated exposure of rats to cocaine resulted in a long-lasting (weeks) sensitization of the hypothalamus-pituitary-adrenal axis, i.e. hypersecretion of adrenocorticotropic hormone and of the glucocorticoid corticosterone. Moreover, we found that the administration of a glucocorticoid receptor antagonist abolished the expression of psychostimulant-induced behavioural sensitization. In the present study we tested whether stressor- or drug-induced long-term hypersecretion of corticosterone is associated with the long-term expression of behavioural sensitization to psychostimulant drugs. To that end, groups of male Wistar rats were exposed once to interleukin-1beta or to footshocks, treatments that are known to induce long-term sensitization of the hypothalamus-pituitary-adrenal axis, or were treated with amphetamine or morphine, according to protocols known to induce long-lasting behavioural (locomotor) sensitization. Three weeks later, the groups and their controls were challenged with amphetamine or vehicle. Previous exposure to interleukin-1beta or footshocks enhanced adrenocorticotropic hormone and corticosterone responses, but did not affect the long-term locomotor sensitization to amphetamine. Prior amphetamine treatment enhanced the locomotor response and the adrenocorticotropic hormone and corticosterone responses to amphetamine. Prior morphine treatment resulted in long-term locomotor sensitization, whereas the adrenocorticotropic hormone and corticosterone responses to amphetamine were decreased. From these findings and the absence of within-group correlation between corticosterone and locomotor responses in interleukin-1beta and morphine-pretreated rats, we conclude that there is no correlation between sensitization of the corticosterone response and behavioural sensitization to amphetamine. Apparently, sensitization of the corticosterone response is not a prerequisite for the long-term expression of behavioural sensitization, which suggests that drug-induced long-term behavioural sensitization may involve corticosteroid receptor-dependent (central) mechanisms that occur independent of hypothalamus-pituitary-adrenal axis responsiveness.