Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in major depression. The physiological alterations underlying reduced dopamine (DA) signaling could result from either diminished DA release from presynaptic neurons or impaired signal transduction, either due to changes in receptor number or function and/or altered intracellular signal processing. There are data supporting each of these mechanisms, although interpretation of previous research is confounded by issues around study population, medication status, and technological limitations. In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure. Animal models of major depression show considerable responsiveness to manipulations of DA neurotransmission. Several studies, including postmortem investigations, particularly of subjects with severe depression, have demonstrated reduced concentrations of DA metabolites both in the cerebrospinal fluid and in brain regions that mediate mood and motivation. Although the neuroimaging findings are not unequivocal, several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possibly reflected by a compensatory up-regulation of D2 receptors. These alterations in DA signaling may underlie the findings of increased “liking” or “high” feelings reported by severely depressed subjects treated with d-amphetamine compared with the response of less severely ill and normal control subjects. The efficacy of medications that directly act on DA neurons or receptors, such as monoamine oxidase inhibitors and pramipexole, suggests that subtypes of depression stemming from a primary DA dysfunction exist. Further research on the contribution of DA to the pathophysiology of depression is justified to improve outcomes for patients with treatment-resistant and nonremitting depression.
Dopaminergic pathways in the human brain. Reprinted with permission from Szabo et al (2004)5 and Sanchez-Gonzalez et al (2005).6 (Brain drawing used with the permission of Robert Finkbeiner.) Note that this image is a midline sagittal section of the brain. Many of the structures identified are located more laterally than the drawing indicates.
Dopaminergic synaptic signaling. Reprinted with permission from Szabo et al (2004).5 AADC indicates aromatic acid decarboxylase; AMPT, α-methylparatyrosine; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; COMT, catechol-O-methyltransferase; D1-D5, dopamine receptors 1 through 5; DA, dopamine; DAT, dopamine transporter; DOPA, 3,4-dihydroxyphenylalanine; DOPAC, dihydroxyphenylacetic acid; Gi, Go, and Gs, protein subunits; HVA, homovanillic acid; MAO, monoamine oxidase; MT, 3-methoxytyramine; TH, tyrosine hydroxylase; and VMAT, vesicular monoamine transporter.
Differing structures of dopamine terminals in the striatum and prefrontal cortex. Reprinted with permission from Sesack et al (1998).14 COMT indicates catechol-O-methyltransferase; DA, dopamine; and NE, norepinephrine.
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