Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants

Lesch, Klaus‐Peter; Aulakh, Charanjit S.; Wolozin, Benjamin; Tolliver, Teresa J.; Hill, James L.; Murphy, Dennis L.

doi:10.1016/0169-328x(93)90069-2

Cited by 203 publications

(97 citation statements)

References 21 publications

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“…The relative abundance of neuronal 5-HT transporter transcript in CA1 pyramidal neurons was also very low (3.5 Ϯ 2.4% in the acute vehicle group). This agrees with immunocytochemical and in situ hybridization studies showing low neuronal 5-HT transporter protein levels in the CA1 hippocampal area (27,28). Finally, mRNA levels for Kv1 were well above the background, but exhibited no steroid dependency (averages for the groups ranged between 20.6 Ϯ 4.2 and 36.3 Ϯ 11.0).…”

Section: -Ht Responsessupporting

confidence: 75%

Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons

Karten

Nair

Essen³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

140

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Recent studies indicated that hyperactivity of the hypothalamopituitary-adrenal system is a considerable risk factor for the precipitation of affective disorders, most notably of major depression. The mechanism by which this hyperactivity eventually leads to clinical symptoms of depression is unknown. In the present animal study, we tested one possible mechanism, i.e., that long-term exposure to high corticosterone levels alters functional responses to serotonin in the hippocampus, an important area in the etiology of depression. Rats were injected daily for 3 weeks with a high dose of corticosterone; electrophysiological responses to serotonin were recorded intracellularly from CA1 pyramidal neurons in vitro. We observed that daily injections with corticosterone gradually attenuate the membrane hyperpolarization and resistance decrease mediated by serotonin-1A receptors. We next used single-cell antisense RNA amplification from identified CA1 pyramidal neurons to resolve whether the functional deficits in serotonin responsiveness are accompanied by decreased expression levels of the serotonin-1A receptor. It appeared that expression of serotonin-1A receptors in CA1 pyramidal cells is not altered; this result was supported by in situ hybridization. Expression of corticosteroid receptors in the same cells, particularly of the high-affinity mineralocorticoid receptor, was significantly reduced after long-term corticosterone treatment. The present findings indicate that prolonged elevation of the corticosteroid concentration, a possible causal factor for major depression in humans, gradually attenuates responsiveness to serotonin without necessarily decreasing serotonin-1A receptor mRNA levels in pyramidal neurons. These functional changes may occur by a posttranscriptional mechanism or by transcriptional regulation of genes other than the serotonin-1A receptor gene itself. mineralocorticoid receptor ͉ glucocorticoid receptor ͉ intracellular recording ͉ single-cell antisense RNA amplification ͉ in situ hybridization C orticosteroid hormones are secreted from the adrenal glands in a circadian pattern (1). In rats, corticosterone circulates in low amounts in the morning and at high concentrations in the evening. Temporary elevations in the level occur after stressful events. Corticosteroids can enter the brain and bind to two intracellular receptor subtypes (2): the mineralocorticoid receptor (MR; K d Ϸ 0.5 nM) and the glucocorticoid receptor (GR; K d Ϸ 5 nM). Because of the difference in affinity, changes in plasma corticosterone concentration alter the relative MR͞GR occupation. Low levels of corticosterone mainly activate brain MRs, whereas high levels at the circadian peak or during stress activate GRs along with MRs (3-5). Electrophysiological studies in CA1 hippocampal neurons, which coexpress MR and GR, have shown that selective activation of corticosteroid receptors alters ion conductances and neurotransmitter responses within 1-2 hours (6). In particular, the membrane hyperpolarization mediated by serotonin-...

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Section: -Ht Responsessupporting

confidence: 75%

Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons

Karten

Nair

Essen³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

140

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“…A new oligonucleotide corresponding to bases 1667-1710 of the human 5-HT transporter cDNA (Lesch et al 1993) was synthesized by GibcoBRL (Grand Island, NY). The sequence of the new probe was determined using the BLAST program (Genetics Computer Group, Madison, WI) in order to maximize specificity by including sequences found in human SERT and to exclude sequences that are in common with the dopamine and norepinephrine transporters.…”

Section: In Situ Hybridization Histochemistry Of Sert Mrnamentioning

confidence: 99%

Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide Victims

Arango

Underwood

Boldrini

et al. 2001

Neuropsychopharmacology

331

228

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Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HTReduced serotonergic function in the brain of suicide victims is suggested based on findings of lower brainstem levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), as well as fewer serotonin transporter (SERT) binding sites and more post-synaptic 5-HT 1A receptors in prefrontal cortex in suicide victims (see Mann et al. 2000 for review). In suicide victims, the changes in SERT and 5-HT 1A binding are NO . 6 Serotonin Transporter in the DRN of Suicides 893 localized to the ventral PFC (Arango et al. 1995), an area involved in behavioral inhibition (Damasio et al. 1994) and, therefore, the potential location of a diathesis for suicidal behavior. Studies in depressed suicide attempters compared to psychiatric controls have found lower cerebrospinal levels of 5-HIAA (Mann and Malone 1997). In vivo studies have employed pharmacological challenges that activate brain serotonin receptors invoking release of prolactin that can be measured in the blood Malone et al. 1996) or a change in regional glucose metabolism in the brain that can be measured by positron emission tomography (Malone et al. 2000). Results of these studies indicate blunted responses to 5-HT and support the notion of serotonin deficiency in depressed suicidal patients. Importantly, the relationship of serotonin hypofunction to suicidal acts is independent of psychiatric diagnosis (Mann et al. 1989;Stanley et al. 2000;Coccaro et al. 1989).The most widely reported serotonergic abnormality in major depression involves fewer platelet serotonin transporter sites (Owens and Nemeroff 1994). In vivo imaging (Malison et al. 1998;Willeit et al. 2000) and postmortem brain studies (Perry et al. 1983;Arango et al. 1995;Mann et al. 2000) conducted in depressed patients suggest that less SERT binding is more widespread in the brain compared with suicides, and includes the brainstem. One potential cause for fewer SERT sites, in the prefrontal cortex and elsewhere, would be a reduction in SERT gene expression. SERT mRNA is expressed in 5-HT neurons in the brainstem.We previously reported (Austin et al. 1994) the first anatomical visualization of human brain serotonin transporter gene expression and described the localization of the SERT mRNA to the serotonergic neurons of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN). In rodents, non-human primates, and presumably humans, it is the dorsal and median raphe nuclei that provide the serotonergic innervation of the entire forebrain (Wilson and Molliver 1991a,b;Bobillier et al. 1975Bobillier et al. , 1976Sakai et al. 1977).In the DRN, the 5-HT 1A receptor is a somatodendritic inhibitory autoreceptor on 5-HT neurons (Vergé et al. 1985;Middlemiss and Fozard 1983). 5-HT released locally acts on the autoreceptor to inhibit further release of the 5-HT transmitter (Wang and Aghajanian 1977). Altered autoinhib...

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“…5-HT clearance is a highly orchestrated process involving regulation of SERT gene transcription-translation (Lesch et al, 1993;Ramamoorthy et al, 1993aRamamoorthy et al, , 1995aNeumaier et al, 1996;Morikawa et al, 1998;Benmansour et al, 1999;Mossner et al, 2001) and posttranslational modification of the transporter (Jayanthi et al, 1994;Miller and Hoffman, 1994;Qian et al, 1997;Ramamoorthy, 2002). The activation of protein kinase C (PKC) and/or inhibition of protein phosphatase regulate SERT (Ramamoorthy et al, 1998a;Bauman et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

A Role for p38 Mitogen-Activated Protein Kinase in the Regulation of the Serotonin Transporter: Evidence for Distinct Cellular Mechanisms Involved in Transporter Surface Expression

Samuvel¹,

Jayanthi²,

Bhat³

et al. 2005

J. Neurosci.

198

260

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Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants

Cited by 203 publications

References 21 publications

Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons

Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons

Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide Victims

A Role for p38 Mitogen-Activated Protein Kinase in the Regulation of the Serotonin Transporter: Evidence for Distinct Cellular Mechanisms Involved in Transporter Surface Expression

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