Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter

Abstract

Considerable evidence has accrued in the last two decades to support the hypothesis that alterations in serotonergic neuronal function in the central nervous system occur in patients with major depression. These findings include the following: (a) reduced cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT) in drug-free depressed patients; (b) reduced concentrations of 5-HT and 5-HIAA in postmortem brain tissue of depressed and (or) suicidal patients; (c) decreased plasma tryptophan concentrations in depressed patients and a profound relapse in remitted depressed patients who have responded to a serotonergic antidepressant when brain tryptophan availability is reduced; (d) in general, all clinically efficacious antidepressants augment 5-HT neurotransmission following chronic treatment; (e) clinically efficacious antidepressant action by all inhibitors of 5-HT uptake; (f) increases in the density of 5-HT2 binding sites in postmortem brain tissue of depressed patients and suicide victims, as well as in platelets of drug-free depressed patients; (g) decreased number of 5-HT transporter (determined with [3H]imipramine or [3H]paroxetine) binding sites in postmortem brain tissue of suicide victims and depressed patients and in platelets of drug-free depressed patients. In our studies, this reduction in platelet 5-HT transporter binding is not due to prior antidepressant treatment of hypercortisolemia and is not observed in mania, Alzheimer disease, schizophrenia, panic disorder, fibromyalgia, or atypical depression. In a pilot study, this deficit predicted treatment response to an experimental antidepressant. These findings support the hypothesis that alterations in 5-HT neurons play a role in the pathophysiology of depression.

The effects of enriched environment on the behavioral and corticosterone response to methamphetamine in adolescent and adult mice

“…MA exposure did not cause any long-term changes in plasma corticosterone levels in either adolescent or adult mice. This finding replicates studies showing no immediate effects (Rud et al, 2016) or long-term effects (Buck et al, 2017) (Aisa, Tordera, Lasheras, Del Rio, & Ramirez, 2007;Hestermann, Temel, Blokland, & Lim, 2014), the dopamine, serotonin, and norepinephrine neurotransmitter systems also influence these behaviors (Carrasco & Van de Kar, 2003;Dunlop & Nemeroff, 2007;Owens & Nemeroff, 1994) and these neurotransmitter systems are altered by MA (Sulzer et al, 2005). Thus, the behavioral effects of MA in the adult mice may be due to MA's effects on these neurotransmitter systems.…”

Serotonin innervation of human basal ganglia

“…Serotonin (5-hydroxytryptamine, 5-HT) is involved in many functions, such as the regulation of the sleep-waking cycle (Steriade, 2004;Jones, 2005;Monti & Jantos, 2008), the modulation of pain signals (Sommer, 2004) and the pathogenesis of mood disorders (Owens & Nemeroff, 1994;Cools et al, 2008). Such a multifaceted role of 5-HT is possible because this monoamine is produced and released by a widely distributed neuronal system that reaches virtually all major brain structures (Parent, 1996).…”

Utility of organotypic raphe slice cultures to investigate the effects of sustained exposure to selective 5‐HT reuptake inhibitors on 5‐HT release

“…Depression is a major health problem around the world, and the lifetime prevalence of major depressive disorder is 10 to 20% (Kessler et al, 2003). Because the sites of action of early types of antidepressant drugs, such as the tricyclic antidepressants and monoamine oxidase inhibitors, lie mostly in the monoaminergic system, major depressive disorder has been associated with hypofunction of the central monoaminergic system, in particular the 5-hydroxytryptaminergic (5-HTergic) system (Owens and Nemeroff, 1994;Belmaker and Agam, 2008). Selective 5-hydroxytryptamine (5-HT, serotonin) reuptake inhibitors (SSRIs) are now one of the more commonly used antidepressant drugs in clinical use.…”