The impact of glucocorticoids on β-amyloid(1–42) (Aβ(1–42)) and NMDA-induced neurodegeneration was investigated in vivo. Aβ(1–42) or NMDA was injected into the cholinergic magnocellular nucleus basalis in adrenalectomized (ADX) rats, ADX rats supplemented with 25%, 100%, 2×100% corticosterone pellets, or sham-ADX controls. Aβ(1–42)- or NMDA-induced damage of cholinergic nucleus basalis neurones was assessed by quantitative acetylcholinesterase histochemistry. Plasma concentrations of corticosterone and cholinergic fibre loss after Aβ(1–42) or NMDA injection showed a clear U-shaped dose–response relationship. ADX and subsequent loss of serum corticosterone potentiated both the Aβ(1–42) and NMDA-induced neurodegeneration. ADX+25% corticosterone resulted in a 10–90 nM plasma corticosterone concentration, which significantly attenuated the Aβ(1–42) and NMDA neurotoxicity. ADX+100% corticosterone (corticosterone concentrations of 110–270 nM) potently decreased both Aβ(1–42)- and NMDA-induced neurotoxic brain damage. In contrast, high corticosterone concentrations of 310–650 nM potentiated Aβ(1–42)- and NMDA-triggered neurodegeneration. In conclusion, chronic low or high corticosterone concentrations increase the vulnerability of cholinergic cells to neurotoxic insult, while slightly elevated corticosterone levels protect against neurotoxic injury. Enhanced neurotoxicity of NMDA in the presence of high concentrations of specific glucocorticoid receptor agonists suggests that the corticosterone effects are mediated by glucocorticoid receptors.