Too much hypothalamic serotonin transporter is bad for your mood

Abstract

The working hypothesis for the biochemical basis of depression — a disabling mood disorder affecting at least 1% of the adult population — is that there is a lasting deficiency of available serotonin in brain regions that control mood. This notion is supported by observations that the most effective anti-depressant drugs, fluoxetine, paroxetine and fluvoxamine, are potent competitive inhibitors of the serotonin transporter (ST), blocking its action at sub-nanomolar concentrations. ST is a transmembrane protein responsible for terminating synaptic serotonin signaling by re-uptake of the released neurotransmitter to the presynaptic terminals. Thus, common wisdom holds that anti-depressant drugs improve mood by blocking the action of synaptic ST, thereby increasing the duration of action of serotonin following its synaptic release.It was long suspected that the reduced brain serotonin availability in depressed patients reflected overexpression of the ST gene or underexpression of genes encoding serotonin-synthesizing enzymes or for certain serotonin receptor subtypes. However, clear conclusions were not available from post-mortem human tissues, since depressive patients are usually on medication for long periods. This, combined with the lack of good animal models for human depression, meant that there were no clear answers. Now, a new study from the Clinic of Child Psychiatry at the University of Oulu, Finland 1xElevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents. Dahlstrom, M et al. Mol. Psychiat. 2000; 5: 514–522Crossref | PubMedSee all References1, reports that hypothalamic/midbrain ST levels in drug-naive depressed children and adolescents are elevated compared with non-depressed patients. The study employed 123I-labeled β-CIT, which strongly binds ST and can be visualized in vivo using single photon emission computerized tomography (SPECT). Such measurements indicated that 24 h following tracer injection, hypothalamic/midbrain ST labeling was 22% higher in depressive patients — a difference seen in both male and female patients.This is the first demonstration of elevated in vivo brain ST levels in depressed humans. Hence, it strongly supports the rationale for using ST blockers as treatment for depression. Notably, a recent study shows that depressed patients differ in their response to anti-depressant drugs depending on their ST promoter genotype, with patients having two copies of the longer ST promoter allele showing improved drug efficacy 2xAllelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Pollock, B.G et al. Neuropsychopharmacology. 2000; 23: 587–590Crossref | PubMed | Scopus (351)See all References2. Apparently, in these patients the limbic ST levels are even higher compared with other depressive patients, or alternatively, more effectively downregulated by anti-depressant drugs. It remains to be seen if such correlations can be visualized in vivo using SPECT.