Effects on plasma corticosterone levels and brain serotonin from interference with methamphetamine-induced corticosterone release in neonatal rats.

Methamphetamine (MA) induces multiple effects in rats including alterations to corticosterone (CORT) and adrenocorticotropic hormone (ACTH). This effect is age dependent showing a U-shaped function similar to that of other stressors during the stress hyporesponsive period. Neonatal MA treatment leads to adult learning and memory impairments, but whether these are related to MA-induced CORT release is unknown. Here in, four methods were tested in neonatal rats previously established in adult rats for inhibiting stress-induced CORT release: inhibiting synthesis (metyrapone (MET) or ketoconazole (KTZ)) or surgically by adrenalectomy or adrenal autotransplantation (ADXA). Pretreatment on postnatal day 11 with MET or KTZ prior to four doses of 10 mg/kg of MA initially suppressed MA-induced increases in plasma CORT, but 24 h later, even with additional inhibitor treatment, a large CORT increase was seen which exceeded that of MA alone. Adrenalectomy blocked MA-induced increases in CORT but caused a secondary effect on brain serotonin (5-HT) and dopamine (DA), causing greater reductions than those caused by MA alone. ADXA inhibited MA-induced CORT release without causing a 24-h CORT increase and did not produce additional effects on brain 5-HT or DA. Neonatal ADXA is a new model for developmental drug or stress experiments designed to test the role of CORT in mediating early effects on later outcomes.