35,36 Some studies have suggested this gene-environment interaction

may be stronger in females than males.35,37 Norepinephrine Norepinephrine (NE) is primarily produced in cells of the pontine locus ceruleus. Similar to 5-HT neurons, these cells project to multiple cortical and subcortical brain regions, many of which have been implicated in the biology of depression. The NE system is well known to modulate Inhibitors,research,lifescience,medical the stress response, and the locus Bosutinib ceruleus receives inputs from several other neurotransmitter systerns providing information about homeostasis (eg, 5-HT, opioids, γ-aminobutyric acid (GABA), corticotropin-releasing factor (CRF), DA, and glutamate). Norepinephrine exerts its effects through Ganetespib interaction with pre- and postsynaptic α- and β-adrenergic receptors. Similarly to 5-HT, following release from the presynaptic nerve terminal, NE is taken back up into the presynaptic terminal by the norepinephrine transporter (NET) where it is Inhibitors,research,lifescience,medical either repackaged or metabolized by MAO. A role for NE in the pathophysiology of depression is

fairly well-established but less clear than for 5-HT. Administration of drugs that deplete NE stores (such as reserpine) can precipitate depressive symptoms – however, such drugs affect stores of other neurotransmitters such as 5-HT and DA. Studies of NE metabolite Inhibitors,research,lifescience,medical levels (primarily 3-methoxy-4-hydroxy-phenylglycol [MHPG]) in the CSF of depressed patients have yielded inconsistent results. Currently, radioligands for the majority of NE receptors and the Inhibitors,research,lifescience,medical NET are not available for use in humans. However, depletion of NE in depressed patients taking noradrenergic antidepressants can result in depressive relapse.38 Further, depleting NE (as well as DA) in euthymic, unmedicated patients with a history of

depression Inhibitors,research,lifescience,medical can precipitate a relapse.39 Suicide victims have been reported to exhibit increased activity of tyrosine hydroxylase, the enzyme that controls the rate-limiting step of synthesis of NE in the locus ceruleus.40 Drugfree depressed patients exhibit a blunted growth hormone response to clonidine, an β2-adrenergic agonist. A role for the NE system in depression is further supported by data on the effects of antidepressant medications in humans and animal models. Selective NE reuptake inhibitors (eg, maprotiline, desipramine, and reboxetine) have all been shown to be efficacious Batimastat in the treatment of depression. Many tricyclic antidepressant (TCA) medications inhibit both NE and 5-HT uptake, including imipramine. So-called non-TCA “dual” reuptake inhibitors, such as duloxetine and venlafaxine, inhibit reuptake of both 5-HT and NE, are effective in treating depression, and have been suggested to be more efficacious overall than certain SSRIs,41,42 though this remains a controversial area. Chronic administration of antidepressant medications or electroconvulsive shock (ECS) are associated with increased noradrenergic neuretransmission.