Critical time-window for the actions of adrenal glucocorticoids in behavioural sensitisation to cocaine.
Glucocorticoids, secreted by the adrenals in response to stress, have profound effects on behavioural responsiveness to psychostimulant drugs. We have studied the critical time-window for the influence of corticosterone on behavioural sensitisation to cocaine in relation to i) the stage of behavioural sensitisation, and ii) the time of drug exposure. Previously, we have identified a mouse strain (DBA/2) in which surgical removal of the adrenals (adrenalectomy) fully prevented locomotor sensitisation to cocaine. To investigate the role of corticosterone in expression of behavioural sensitisation, the glucocorticoid receptor antagonist mifepristone (RU38486) was administered to previously sensitised mice prior to a cocaine challenge. Furthermore, adrenalectomised mice were given corticosterone replacement at different intervals prior to each drug administration, to investigate the role of the glucocorticoid in initiation of behavioural sensitisation, and in relation to the time of drug exposure. Administration of mifepristone to previously sensitised animals failed to block expression of cocaine-induced behavioural sensitisation. In adrenalectomised mice, intermittent replacement of corticosterone (1 mg/kg i.p., either 2 h or 5 min prior to each cocaine administration), did not reverse the sensitisation deficit. By contrast, chronic corticosterone replacement (20% pellet) partially restored initiation of behavioural sensitisation. These data indicate that the presence of corticosterone facilitates the initiation rather than the expression of behavioural sensitisation to cocaine. However, because high corticosterone concentrations only partially reversed the sensitisation deficit of adrenalectomised mice, the adrenal glucocorticoid seems necessary, but not sufficient, for full behavioural sensitisation to cocaine in the DBA/2 strain.
de Jong
Inge E M
IE
Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, Division of Medical Pharmacology, Gorlaeus Laboratories, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
de Kloet
E Ronald
ER
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000315:Adrenalectomy; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects*; D003345:Corticosterone / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D015735:Mifepristone / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013997:Time Factors
D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003042:Cocaine; D003345:Corticosterone