Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter

Kim, Dong Kyu; Tolliver, Teresa J.; Huang, Shar-yin N.; Martin, Bradley J.; Andrews, Anne M.; Wichems, Christine H.; Holmes, Andrew; Lesch, Klaus‐Peter; Murphy, Dennis L.

doi:10.1016/j.neuropharm.2005.08.010

Cited by 170 publications

(157 citation statements)

References 61 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…These results are in agreement with previous biochemical determinations of TPH activity in animals treated with substituted amphetamines (see Gibb et al, 1994), and indicate that cytoplasmic as well as membranous serotonergic proteins are lost after MDMA exposure. In addition, the loss of TPH after MDMA indicates that the profile of lasting serotonergic deficits after substituted amphetamines differs from that in SERT-null animals which have normal TPH levels, but, in the absence of the SERT protein, develop apparent neuroadaptive changes in 5-HT metabolism (Bengel et al, 1998;Kim et al, 2005) (Table 1). Hence, in conjunction with loss of SERT protein, our TPH results mitigate against the notion that decrements in 5-HT and SERT-IR axons visualized with antisera 1 and antisera 2 in the cerebral (parietal) cortex of representative control rats (a, b) and rats previously treated with 5,7-DHT (c, d) or MDMA (e, f).…”

Section: Discussionmentioning

confidence: 99%

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Xie

Tong

McLane

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

We studied in vivo expression of the serotonin transporter (SERT) protein after 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine (PCA), or fenfluramine (FEN) treatments, and compared the effects of substituted amphetamines to those of 5,7-dihydroxytryptamine (5,7-DHT), an established serotonin (5-HT) neurotoxin. All drug treatments produced lasting reductions in 5-HT, 5-HIAA, and [ 3 H]paroxetine binding, but no significant change in the density of a 70 kDa band initially thought to correspond to the SERT protein. Additional Western blot studies, however, showed that the 70 kDa band did not correspond to the SERT protein, and that a diffuse band at 63-68 kDa, one that had the anticipated regional brain distribution of SERT protein (midbrain4 striatum4neocortex4cerebellum), was reduced after 5,7-DHT and was absent in SERT-null animals, was decreased after MDMA, PCA, or FEN treatments. In situ immunocytochemical (ICC) studies with the same two SERT antisera used in Western blot studies showed loss of SERT-immunoreactive (IR) axons after 5,7-DHT and MDMA treatments. In the same animals, tryptophan hydroxylase (TPH)-IR axon density was comparably reduced, indicating that serotonergic deficits after substituted amphetamines differ from those in SERT-null animals, which have normal TPH levels but, in the absence of SERT, develop apparent neuroadaptive changes in 5-HT metabolism. Together, these results suggest that lasting serotonergic deficits after MDMA and related drugs are unlikely to represent neuroadaptive metabolic responses to changes in SERT trafficking, and favor the view that substituted amphetamines have the potential to produce a distal axotomy of brain 5-HT neurons.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Xie

Tong

McLane

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Contrary to the observation on 5HTT expression studies (Lesch et al, 1996), Hanna et al (1998) reported association of the long variant allele with higher plasma serotonin level. Meanwhile, another recent study showed altered serotonin synthesis and turnover using mice with genetic disruption of 5-HTT (Kim et al, 2005). Thus alternatively, the increased 5-HIAA concentration in S/S genotype could be due to increased serotonin synthesis or turnover.…”

Section: Discussionmentioning

confidence: 99%

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

Kishida

Aklillu

Kawanishi

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

The serotonin (5-hydroxytryptamine) transporter (5-HTT) is considered to affect the pathogenesis of mood disorders. Large number of genetic association studies between 5-HTT functional polymorphisms and vulnerability of mood disorders and therapeutic response to antidepressants has been carried out. We investigated the influence of 5-HTT-linked polymorphic region (5-HTTLPR) and 5-HTT 17 bp variable number of tandem repeat polymorphism (5-HTTVNTR) polymorphisms on concentrations of monoamine metabolites in cerebrospinal fluid (CSF) among treatment-resistant patients with mood disorders. Subjects were 119 Swedish patients with persistent mood disorders and 141 healthy subjects. In 112 of these patients, we measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol in CSF. Genotyping for 5-HTT polymorphisms from genomic DNA was carried out by PCR. There was no significant difference in allele/genotype frequency between patients and healthy subjects. In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p ¼ 0.03). Although the 5-HIAA concentration showed a tendency to be higher in short (S) carriers than in non-S carriers of the 5-HTTLPR in patients (p ¼ 0.06), when considering patients with major depressive disorder (MDD), the 5-HIAA concentration was significantly higher among S carriers than among non-S carriers (p ¼ 0.02). Moreover, the 5-HIAA concentration was higher in S/S subjects compared to long (L)/L (p ¼ 0.0001) and L/S (p ¼ 0.002) subjects in patients with MDD. Similarly, there was higher HVA concentration in S/S subjects compared to L/L (p ¼ 0.002) and L/S subjects (p ¼ 0.002). There was no effect of 5-HTTVNTR. Our findings show that the 5-HTTLPR polymorphism affects 5-HIAA and HVA concentrations among treatment-resistant patients with mood disorders.

show abstract

“…111 This finding has been followed by several replications in European samples. 112,113 However, findings in Asian and American samples have been inconsistent, including findings of effect in the opposite direction in Korean samples 114,115 and of no association with antidepressant response in a large multicentre USA study. 116 These differential findings suggest that there is no direct association of antidepressant repose and the 5-HTTLPR.…”

Section: Serotonin Transporter Gene-environment Interaction R Uher Anmentioning

confidence: 99%

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

2007

View full text Add to dashboard Cite

Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter

Cited by 170 publications

References 61 publications

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

Contact Info

Product

Resources

About