The cholinergic-adrenergic hypothesis of depression reexamined using clonidine, metoprolol, and physostigmine in an animal model

The role of central nervous system (CNS) cholinergic and noradrenergic mechanisms in the pathogenesis of depression and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is examined using the Behavioral Despair rat model of depression. Immobility (IM), the analog of depression in this model, and plasma corticosterone (C) were increased by physostigmine (PHYSO). Neostigmine (NEO), which does not cross the blood-brain barrier, produced the same peripheral cholinomimetic effects and motor inhibition as PHYSO, but did not change IM. PHYSO's effects on C and IM were blocked by metoprolol pretreatment and partially blocked by clonidine pretreatment. PHYSO increased acetylcholine in the striatum. In this animal model of depression, cholinergic and noradrenergic mechanisms are interactively involved in the regulation of behavioral depression and the HPA axis.