Bi-directional Modulation of Bed Nucleus of Stria Terminalis Neurons by 5-HT: Molecular Expression and Functional Properties of Excitatory 5-HT Receptor Subtypes

Overview

Journal Neuroscience

Specialty Neurology

Date 2009 Sep 26

PMID 19778589

Citations 37

Authors

J-D Guo

S E Hammack

R Hazra

L Levita

D G Rainnie

Affiliations

Soon will be listed here.

Abstract

Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNST(ALG)) plays an important role in mediating the behavioral response to stressful and anxiogenic stimuli. Application of 5-HT elicits complex postsynaptic responses in BNST(ALG) neurons, which includes (1) membrane hyperpolarization (5-HT(Hyp)), (2) hyperpolarization followed by depolarization (5-HT(Hyp-Dep)), (3) depolarization (5-HT(Dep)) or (4) no response (5-HT(NR)). We have shown that the inhibitory response is mediated by activation of postsynaptic 5-HT(1A) receptors. Here, we used a combination of in vitro whole-cell patch-clamp recording and single cell reverse transcriptase polymerase chain reaction (RT-PCR) to determine the pharmacological properties and molecular profile of 5-HT receptor subtypes mediating the excitatory response to 5-HT in BNST(ALG) neurons. We show that the depolarizing component of both the 5-HT(Hyp/Dep) and the 5-HT(Dep) response was mediated by activation of 5-HT(2A), 5-HT(2C) and/or 5-HT(7) receptors. Single cell RT-PCR data revealed that 5-HT(7) receptors (46%) and 5-HT(1A) receptors (41%) are the most prevalent receptor subtypes expressed in BNST(ALG) neurons. Moreover, 5-HT receptor subtypes are differentially expressed in type I-III BNST(ALG) neurons. Hence, 5-HT(2C) receptors are almost exclusively expressed by type III neurons, whereas 5-HT(7) receptors are expressed by type I and II neurons, but not type III neurons. Conversely, 5-HT(2A) receptors are found predominantly in type II neurons. Finally, bi-directional modulation of individual neurons occurs only in type I and II neurons. Significantly the distribution of 5-HT receptor subtypes in BNST(ALG) neurons predicted the observed expression pattern of 5-HT responses determined pharmacologically. Together, these results suggest that 5-HT can differentially modulate the excitability of type I-III neurons, and further suggest that bi-directional modulation of BNST(ALG) neurons occurs primarily through an interplay between 5-HT(1A) and 5-HT(7) receptors. Hence, modulation of 5-HT(7) receptor activity in the BNST(ALG) may offer a novel avenue for the design of anxiolytic medications.

Citing Articles

The role and mechanism of 5-HTDRN-BNST neural circuit in anxiety and fear lesions.

Zheng X, Dingpeng L, Yan X, Yao X, Wang Y Front Neurosci. 2024; 18:1362899.

PMID: 38784088 PMC: 11111893. DOI: 10.3389/fnins.2024.1362899.

The role of brain serotonin signaling in excessive alcohol consumption and withdrawal: A call for more research in females.

Castle M, Flanigan M Neurobiol Stress. 2024; 30:100618.

PMID: 38433994 PMC: 10907856. DOI: 10.1016/j.ynstr.2024.100618.

Bed Nucleus of the Stria Terminalis (BNST) neurons containing the serotonin 5HT receptor modulate operant alcohol self-administration behavior in mice.

Flanigan M, Gianessi C, Castle M, Dorlean W, Sides T, Kash T Neuropsychopharmacology. 2023; 49(4):709-719.

PMID: 37884740 PMC: 10876660. DOI: 10.1038/s41386-023-01753-7.

Subcortical serotonin 5HT receptor-containing neurons sex-specifically regulate binge-like alcohol consumption, social, and arousal behaviors in mice.

Flanigan M, Hon O, DAmbrosio S, Boyt K, Hassanein L, Castle M Nat Commun. 2023; 14(1):1800.

PMID: 37002196 PMC: 10066391. DOI: 10.1038/s41467-023-36808-2.

Exercise reduces the anxiogenic effects of meta-chlorophenylpiperazine: The role of 5-HT2C receptors in the bed nucleus of the stria terminalis.

Fox J, Boucher M, Abedrabbo K, Hare B, Grimmig B, Falls W Front Synaptic Neurosci. 2023; 14:1067420.

PMID: 36713088 PMC: 9880271. DOI: 10.3389/fnsyn.2022.1067420.

References

Summers C, Kampshoff J, Ronan P, Lowry C, Prestbo A, Korzan W . Monoaminergic activity in subregions of raphé nuclei elicited by prior stress and the neuropeptide corticotropin-releasing factor. J Neuroendocrinol. 2003; 15(12):1122-33. DOI: 10.1111/j.1365-2826.2003.01108.x. View

Tokarski K, Zahorodna A, Bobula B, Hess G . 5-HT7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons. Brain Res. 2003; 993(1-2):230-4. DOI: 10.1016/j.brainres.2003.09.015. View

Day H, Greenwood B, Hammack S, Watkins L, Fleshner M, Maier S . Differential expression of 5HT-1A, alpha 1b adrenergic, CRF-R1, and CRF-R2 receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. J Comp Neurol. 2004; 474(3):364-78. PMC: 2430888. DOI: 10.1002/cne.20138. View

Amat J, Matus-Amat P, Watkins L, Maier S . Escapable and inescapable stress differentially alter extracellular levels of 5-HT in the basolateral amygdala of the rat. Brain Res. 1998; 812(1-2):113-20. DOI: 10.1016/s0006-8993(98)00960-3. View

Ballaz S, Akil H, Watson S . The 5-HT7 receptor: role in novel object discrimination and relation to novelty-seeking behavior. Neuroscience. 2007; 149(1):192-202. DOI: 10.1016/j.neuroscience.2007.07.043. View

Zhou F, Hablitz J . Activation of serotonin receptors modulates synaptic transmission in rat cerebral cortex. J Neurophysiol. 1999; 82(6):2989-99. DOI: 10.1152/jn.1999.82.6.2989. View

Fernandes C, McKittrick C, File S, McEwen B . Decreased 5-HT1A and increased 5-HT2A receptor binding after chronic corticosterone associated with a behavioural indication of depression but not anxiety. Psychoneuroendocrinology. 1997; 22(7):477-91. DOI: 10.1016/s0306-4530(97)00052-8. View

Puig M, Celada P, Shapiro D, Roth B, Mengod G, Artigas F . Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci. 2001; 21(24):9856-66. PMC: 6763049. View

Handley S, McBlane J, Critchley M, Njunge K . Multiple serotonin mechanisms in animal models of anxiety: environmental, emotional and cognitive factors. Behav Brain Res. 1993; 58(1-2):203-10. DOI: 10.1016/0166-4328(93)90104-x. View

10.

Lowry C . Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis. J Neuroendocrinol. 2002; 14(11):911-23. DOI: 10.1046/j.1365-2826.2002.00861.x. View

11.

Aston-Jones G, Harris G . Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology. 2004; 47 Suppl 1:167-79. DOI: 10.1016/j.neuropharm.2004.06.020. View

12.

Duncan G, Johnson K, Breese G . Topographic patterns of brain activity in response to swim stress: assessment by 2-deoxyglucose uptake and expression of Fos-like immunoreactivity. J Neurosci. 1993; 13(9):3932-43. PMC: 6576454. View

13.

Zhang Y, Gray T, DSouza D, Carrasco G, Damjanoska K, Dudas B . Desensitization of 5-HT1A receptors by 5-HT2A receptors in neuroendocrine neurons in vivo. J Pharmacol Exp Ther. 2004; 310(1):59-66. DOI: 10.1124/jpet.103.062224. View

14.

Hedlund P, Sutcliffe J . The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder. Neurosci Lett. 2007; 414(3):247-51. PMC: 1849956. DOI: 10.1016/j.neulet.2006.12.054. View

15.

Ju G, Swanson L, Simerly R . Studies on the cellular architecture of the bed nuclei of the stria terminalis in the rat: II. Chemoarchitecture. J Comp Neurol. 1989; 280(4):603-21. DOI: 10.1002/cne.902800410. View

16.

Walker D, Cassella J, Lee Y, De Lima T, Davis M . Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle. Neurosci Biobehav Rev. 1998; 21(6):743-53. DOI: 10.1016/s0149-7634(96)00061-9. View

17.

Waeber C, Sebben M, Nieoullon A, Bockaert J, Dumuis A . Regional distribution and ontogeny of 5-HT4 binding sites in rodent brain. Neuropharmacology. 1994; 33(3-4):527-41. DOI: 10.1016/0028-3908(94)90084-1. View

18.

Egli R, Winder D . Dorsal and ventral distribution of excitable and synaptic properties of neurons of the bed nucleus of the stria terminalis. J Neurophysiol. 2003; 90(1):405-14. DOI: 10.1152/jn.00228.2003. View

19.

Gray T, Magnuson D . Peptide immunoreactive neurons in the amygdala and the bed nucleus of the stria terminalis project to the midbrain central gray in the rat. Peptides. 1992; 13(3):451-60. DOI: 10.1016/0196-9781(92)90074-d. View

20.

Riad M, Wu C, Singh S, Descarries L . Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol. 1999; 409(2):187-209. DOI: 10.1002/(sici)1096-9861(19990628)409:2<187::aid-cne2>3.0.co;2-p. View