Organic Cation Transporter Inhibition Increases Medial Hypothalamic Serotonin Under Basal Conditions and During Mild Restraint

Overview

Journal Brain Res

Specialty Neurology

Date 2010 Feb 23

PMID 20171957

Citations 15

Authors

Na Feng

Christopher A Lowry

Jodi L Lukkes

Miles Orchinik

Gina L Forster

Kenneth J Renner

Affiliations

Soon will be listed here.

Abstract

The dorsomedial hypothalamus (DMH) has been implicated in the coordination of stress responses. Restraint stress or systemic corticosterone (CORT) treatment induces a rapid increase in tissue concentrations of serotonin (5-hydroxytryptamine; 5-HT) in the DMH. Although the mechanism for rapid changes in 5-HT concentrations in the DMH is not clear, earlier results suggest that stress-induced increases in CORT may inhibit 5-HT transport from the extracellular fluid by acting on corticosterone-sensitive organic cation transporters (OCTs). We tested the hypothesis that perfusion of the medial hypothalamus (MH), which includes the DMH, with the OCT blocker decynium 22 (D-22) would potentiate the effects of mild restraint on extracellular 5-HT. Male Sprague-Dawley rats, implanted with a microdialysis probe into the MH, were treated with reverse-dialysis of D-22 (20 microM; 40 min) or vehicle and subjected to either 40 min mild restraint or undisturbed control conditions. Perfusates collected from a separate group of rats were evaluated for the effect of restraint on extracellular CORT concentrations in the MH. Reverse-dialysis of D-22 induced an increase (200%) in extracellular 5-HT concentrations in the MH in undisturbed control rats. Restraint in the absence of D-22 did not significantly affect MH CORT or 5-HT concentrations. However, perfusion of the MH with D-22 during restraint led to an increased magnitude and duration of extracellular 5-HT concentrations, relative to D-22 by itself. These results are consistent with the hypothesis that OCTs in the DMH contribute to the clearance of 5-HT from the extracellular fluid under both baseline conditions and mild restraint.

Citing Articles

Corticosterone rapidly modulates dorsomedial hypothalamus serotonin and behavior in an estrogen- and progesterone-dependent manner in adult female rats: potential role of organic cation transporter 3 (OCT3).

Scholl J, Rogers J, Feng N, Forster G, Watt M, Yaeger J Stress. 2025; 28(1):2457765.

PMID: 39898528 PMC: 11801257. DOI: 10.1080/10253890.2025.2457765.

All the brain's a stage for serotonin: the forgotten story of serotonin diffusion across cell membranes.

Andrews P, Bosyj C, Brenton L, Green L, Gasser P, Lowry C Proc Biol Sci. 2022; 289(1986):20221565.

PMID: 36321487 PMC: 9627707. DOI: 10.1098/rspb.2022.1565.

Organic Cation Transporters in Psychiatric Disorders.

Daws L Handb Exp Pharmacol. 2021; 266:215-239.

PMID: 34282486 PMC: 9281871. DOI: 10.1007/164_2021_473.

Genetic and Epigenetic Regulation of Organic Cation Transporters.

Kolz C, Schaeffeler E, Schwab M, Nies A Handb Exp Pharmacol. 2021; 266:81-100.

PMID: 33674913 DOI: 10.1007/164_2021_450.

Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter.

Fraser-Spears R, Krause-Heuer A, Basiouny M, Mayer F, Manishimwe R, Wyatt N Eur J Pharmacol. 2018; 842:351-364.

PMID: 30473490 PMC: 6440482. DOI: 10.1016/j.ejphar.2018.10.028.

References

Vialou V, Balasse L, Callebert J, Launay J, Giros B, Gautron S . Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem. 2008; 106(3):1471-82. DOI: 10.1111/j.1471-4159.2008.05506.x. View

Amphoux A, Vialou V, Drescher E, Bruss M, Mannoury la Cour C, Rochat C . Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006; 50(8):941-52. DOI: 10.1016/j.neuropharm.2006.01.005. View

Mo B, Feng N, Renner K, Forster G . Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors. Brain Res Bull. 2008; 76(5):493-8. PMC: 2474795. DOI: 10.1016/j.brainresbull.2008.02.011. View

Zhou M, Engel K, Wang J . Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain. Biochem Pharmacol. 2006; 73(1):147-54. PMC: 1828907. DOI: 10.1016/j.bcp.2006.09.008. View

Kitaichi K, Fukuda M, Nakayama H, Aoyama N, Ito Y, Fujimoto Y . Behavioral changes following antisense oligonucleotide-induced reduction of organic cation transporter-3 in mice. Neurosci Lett. 2005; 382(1-2):195-200. DOI: 10.1016/j.neulet.2005.03.014. View

Inazu M, Takeda H, Matsumiya T . Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J Neurochem. 2002; 84(1):43-52. DOI: 10.1046/j.1471-4159.2003.01566.x. View

Shintani F, Nakaki T, Kanba S, Sato K, Yagi G, Shiozawa M . Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat. J Neurosci. 1995; 15(3 Pt 1):1961-70. PMC: 6578119. View

Bailey T, Nicol G, Schild J, DiMicco J . Synaptic and membrane properties of neurons in the dorsomedial hypothalamus. Brain Res. 2003; 985(2):150-62. DOI: 10.1016/s0006-8993(03)03047-6. View

Shimizu N, Take S, Hori T, Oomura Y . In vivo measurement of hypothalamic serotonin release by intracerebral microdialysis: significant enhancement by immobilization stress in rats. Brain Res Bull. 1992; 28(5):727-34. DOI: 10.1016/0361-9230(92)90252-s. View

10.

Zaretskaia M, Zaretsky D, Sarkar S, Shekhar A, DiMicco J . Induction of Fos-immunoreactivity in the rat brain following disinhibition of the dorsomedial hypothalamus. Brain Res. 2008; 1200:39-50. PMC: 2323830. DOI: 10.1016/j.brainres.2008.01.018. View

11.

Lowry C, Burke K, Renner K, Moore F, Orchinik M . Rapid changes in monoamine levels following administration of corticotropin-releasing factor or corticosterone are localized in the dorsomedial hypothalamus. Horm Behav. 2001; 39(3):195-205. DOI: 10.1006/hbeh.2001.1646. View

12.

DiMicco J, Samuels B, Zaretskaia M, Zaretsky D . The dorsomedial hypothalamus and the response to stress: part renaissance, part revolution. Pharmacol Biochem Behav. 2002; 71(3):469-80. DOI: 10.1016/s0091-3057(01)00689-x. View

13.

Grundemann D, Koster S, Kiefer N, Breidert T, Engelhardt M, Spitzenberger F . Transport of monoamine transmitters by the organic cation transporter type 2, OCT2. J Biol Chem. 1998; 273(47):30915-20. DOI: 10.1074/jbc.273.47.30915. View

14.

Verleysdonk S, Hamprecht B, Rapp M, Wellard J . Uptake and metabolism of serotonin by ependymal primary cultures. Neurochem Res. 2004; 29(9):1739-47. DOI: 10.1023/b:nere.0000035810.08543.97. View

15.

Vialou V, Amphoux A, Zwart R, Giros B, Gautron S . Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J Neurosci. 2004; 24(11):2846-51. PMC: 6729503. DOI: 10.1523/JNEUROSCI.5147-03.2004. View

16.

Culman J, Kvetnansky R, Torda T, MURGAS K . Serotonin concentration in individual hypothalamic nuclei of rats exposed to acute immobilization stress. Neuroscience. 1980; 5(8):1503-6. DOI: 10.1016/0306-4522(80)90012-3. View

17.

Hiasa M, Matsumoto T, Komatsu T, Moriyama Y . Wide variety of locations for rodent MATE1, a transporter protein that mediates the final excretion step for toxic organic cations. Am J Physiol Cell Physiol. 2006; 291(4):C678-86. DOI: 10.1152/ajpcell.00090.2006. View

18.

Wu X, Kekuda R, Huang W, Fei Y, Leibach F, Chen J . Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem. 1998; 273(49):32776-86. DOI: 10.1074/jbc.273.49.32776. View

19.

Commons K, Connolley K, Valentino R . A neurochemically distinct dorsal raphe-limbic circuit with a potential role in affective disorders. Neuropsychopharmacology. 2003; 28(2):206-15. DOI: 10.1038/sj.npp.1300045. View

20.

Ter Horst G, Luiten P . The projections of the dorsomedial hypothalamic nucleus in the rat. Brain Res Bull. 1986; 16(2):231-48. DOI: 10.1016/0361-9230(86)90038-9. View