Antidepressant drugs have clinical efficacy only after long-term administration. Symptoms observed during psychological depression have been attributed to a deficiency or imbalance of norepinephrine (NE) in the CNS; therefore; antidepressant drug-induced regulation of NE responsive adrenergic receptors has been postulated as a mechanism of action in combatting depression. Adrenergic receptors play an important role in the regulation of NE release from neurons. The proinflammatory cytokine tumor necrosis factor-a (TNF), also, not only regulates NE release, but alters adrenergic receptor behavior. Antidepressant administration induces both an increase in TNFa production and an a2-adrenergic receptor dependent switch in noradrenergic sensitivity to TNFa that increases NE release. The goal of the present application is to investigate the role of the interaction between the a2-adrenergic autoreceptor and levels of TNFa in the brain. These studies will evaluate how transient and persistent, modifications in TNFa expression in specific brain regions are associated with changes in a2-adrenergic autoreceptor response from inhibition of NE release to stimulation. The investigators will study the ability of agents that exhibit acute effects on serotonergic or noradrenergic neurons to regulate TNFa generation concurrent with altering presynaptic a2-adrenergic and TNFa sensitivity. In particular, they will examine presynaptic sensitivity to TNFa and dependence on a2-adrenergic receptor activation before and after antidepressant drug administration, as well as drugs that effect NE levels but are not antidepressants. These interactions between TNFa and noradrenergic neurons have led the investigators to hypothesize that aberrant noradrenergic neuronal function, secondary to remodelling between noradrenergic sensitivity to TNFa, and presynaptic a2-adrenergic receptor, plays an important role in the etiology of endogenous depression, and possibly all depressed mood states. In addition, a mechanism of action of drugs, effacious in the treatment of depression, may involve re-establishing a relationship between TNFa levels and a2-adrenergic receptor responses. The continual remodeling of a2-adrenergic autoreceptor function on noradrenergic axon terminals provokes synaptic plasticity. The investigators propose to examine TNFa generation and release, and the role of TNFa in NE release by assessing presynaptic responsiveness to TNFa and the interaction of presynaptic a2-adrenergic receptors in response to the amount and duration of antidepressant drug administration. The investigators believe this study will demonstrate a role for TNF in the treatment of endogenous depression. The changes in presynaptic responsiveness to TNFa during antidepressant drug administration describe a mechanism of action for their delayed clinical effects as well as a novel mechanism of neurophysiology.