Behavioural and biochemical evidence that glucocorticoids are not involved in DOI-elicited 5-HT2 receptor down-regulation

doi:10.1016/0014-2999(93)90670-D

European Journal of Pharmacology

Volume 249, Issues 1–2, 2 November 1993, Pages 117-120

https://doi.org/10.1016/0014-2999(93)90670-D Get rights and content

Abstract

Numerous studies have brought evidence for reciprocal relationships between glucocorticoids and 5-HT₂ receptors; however, whether glucocorticoids affect 5-HT₂ receptor regulation is still unknown. Herein, we have analyzed whether 5-HT₂ receptor down-regulation following repeated administration of the 5-HT₂/5-HT_1C receptor agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) is affected by glucocorticoid removal. Compared with sham surgery, adrenalectomy (11–15 days before-hand) did not affect either frontal cortex [³H]ketanserin binding nor the number of head shakes elicited by a single administration of DOI (2.5 mg/kg s.c.). Pretreatment with DOI (2.5 mg/kg s.c. × 4 in 48 h) decreased to similar extents the head shake response to DOI injection in sham (−88%) and adrenalectomised (−95%) rats. Confirmingly, this paradigm was found to diminish the B_max for [³H]ketanserin binding in sham and adrenalectomised rats by 64% and 46%, respectively. From these data, it is concluded that glucocorticoid removal does not alter 5-HT₂ receptor binding and function nor does it affect 5-HT₂ receptor down-regulation.

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Cited by (21)

Tolerance to LSD and DOB induced shaking behaviour: Differential adaptations of frontocortical 5-HT<inf>2A</inf> and glutamate receptor binding sites
2015, Behavioural Brain Research
Citation Excerpt :
In the current work, we address the tolerance phenomenon characteristic for repeated hallucinogen application [for a review see 5, 33, 34]. Tolerance to hallucinogen induced shaking behaviour has often been associated with a downregulation of frontocortical 5-HT2(A) receptors [35–39]. However, mathematical correlations for this receptor-behaviour association, apart from one study on antagonist related regulation of both parameters [40], have not been presented.
Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT_2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT_2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [³H]spiroperidol and DOB induced [³⁵S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT_2A binding sites and 5-HT₂ signalling, respectively; glutamate-sensitive [³H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT₂ signalling and 5-HT_2A binding, respectively, are not or only marginally affected, yet [³H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT_2A (r = .80) as well as the unchanged [³H]glutamate binding sites (r = .84); tolerance to LSD, as opposed, shares variance with the reduction in [³H]glutamate binding sites only (r = .86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT_2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT_2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT_2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex.
Bi-directional modulation of bed nucleus of stria terminalis neurons by 5-HT: molecular expression and functional properties of excitatory 5-HT receptor subtypes
2009, Neuroscience
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-HT₇ receptors. Single cell RT–PCR data revealed that 5-HT₇ 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-HT₇ 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-HT₇ receptors. Hence, modulation of 5-HT₇ receptor activity in the BNST_ALG may offer a novel avenue for the design of anxiolytic medications.
5-HT<inf>2A</inf> and 5-HT<inf>2C</inf> receptors and their atypical regulation properties
2003, Life Sciences
The 5-HT_2A and 5-HT_2C receptors belong to the G-protein-coupled receptor (GPCR) superfamily. GPCRs transduce extracellular signals to the interior of cells through their interaction with G-proteins. The 5-HT_2A and 5-HT_2C receptors mediate effects of a large variety of compounds affecting depression, schizophrenia, anxiety, hallucinations, dysthymia, sleep patterns, feeding behaviour and neuro-endocrine functions. Binding of such compounds to either 5-HT₂ receptor subtype induces processes that regulate receptor sensitivity. In contrast to most other receptors, chronic blockade of 5-HT_2A and 5-HT_2C receptors leads not to an up- but to a (paradoxical) down-regulation. This review deals with published data involving such non-classical regulation of 5-HT_2A and 5-HT_2C receptors obtained from in vivo and in vitro studies. The underlying regulatory processes of the agonist-induced regulation of 5-HT_2A and 5-HT_2C receptors, commonly thought to be desensitisation and resensitisation, are discussed. The atypical down-regulation of both 5-HT₂ receptor subtypes by antidepressants, antipsychotics and 5-HT₂ antagonists is reviewed. The possible mechanisms of this paradoxical down-regulation are discussed, and a new hypothesis on possible heterologous regulation of 5-HT_2A receptors is proposed.
Serotonin and the Neuroendocrine Regulation of the Hypothalamic-Pituitary-Adrenal Axis in Health and Disease
2003, Vitamins and Hormones
Serotonin (5-hydroxytryptamine, 5-HT)-containing neurons in the midbrain directly innervate corticotropin-releasing hormone (CRH)-containing cells located in paraventricular nucleus of the hypothalamus. Serotonergic inputs into the paraventricular nucleus mediate the release of CRH, leading to the release of adrenocorticotropin, which triggers glucocorticoid secretion from the adrenal cortex. 5-HT_1A and 5-HT_2A receptors are the main receptors mediating the serotonergic stimulation of the hypothalamic–pituitary–adrenal axis. In turn, both CRH and glucocorticoids have multiple and complex effects on the serotonergic neurons. Therefore, these two systems are interwoven and communicate closely. The intimate relationship between serotonin and the hypothalamic–pituitary–adrenal axis is of great importance in normal physiology such as circadian rhythm and stress, as well as pathophysiological disorders such as depression, anxiety, eating disorders, and chronic fatigue. © 2003, Elsevier Science (USA).
Central 5-HT<inf>1</inf> and 5-HT<inf>2</inf> binding sites in transgenic mice with reduced glucocorticoid receptor number
2000, Brain Research
Citation Excerpt :
The binding of [125I]DOI to 5-HT2 sites is found to be increased in two hippocampal areas in GR-deficient mice. 5-HT2A and/or 5-HT2C expression, binding, or functions were previously shown to be either left unchanged or increased after ADX [10,13,22,29,30,36]. In contrast to what was observed for 5-HT1A and 5-HT1B receptors, chronic activation of GR — alone or in combination with MR — in different experimental designs also led to either no change or increases in 5-HT2 receptor activity [15,28–30,38,45,59].
Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used in order to clarify the role of glucocorticoid receptors in the regulation of 5-HT_1A, 5-HT_1nonA and 5-HT₂ binding sites labelled by quantitative autoradiography in the frontal and prefrontal cortex, striatum, hypothalamus, amygdala and raphe nuclei. We found that 1 nM [³H]8-hydroxy-2-[di-N-propylamino]tetralin ([³H]8-OH-DPAT) binding to 5-HT_1A sites was decreased in strata oriens (−15.1±3.5%) and radiatum–lacunosum–moleculare (−13.3±4.3%) of the hippocampal CA₃ area, and 2 nM [³H]5-hydroxytryptamine binding to 5-HT_1nonA sites in the presence of 100 nM 8-OH-DPAT and mesulergine was decreased in the dorsal subiculum (−17.8±6.9%). By contrast, 5-HT₂ sites labelled by 0.5 nM of (±)-1-(2,5-dimethoxy-4-[¹²⁵I]iodophenyl)-2-aminopropane was increased in the dorsal subiculum (+35.2±11.5%) and CA₂ area (+29.2±11.3%). The observed differences in binding to 5-HT₁ and 5-HT₂ sites were all located in areas of the hippocampus that contain both gluco- and mineralo-corticoid receptors, and no difference was observed in anatomical structures which contain only glucocorticoid receptors. Therefore, it seems that the important factor for the regulation of these 5-HT receptors is the interaction between gluco- and mineralo-corticoid receptors rather than the absolute density of glucocorticoid receptors. These results suggest that some of the alterations of the serotonergic neurotransmission observed in depressed patients might be secondary to an altered glucocorticoid receptor function.
The influence of corticosterone on serotonergic stereotypy and sexual behavior in the female rat
1999, Behavioural Brain Research
The effects of adrenalectomy and chronic corticosterone treatment on sexual behavior in the ovariectomized female rat were investigated. The serotonergic type 2A (5-HT_2A) receptor-mediated behavior ‘wet dog shakes’ (WDS) was measured concurrently. In Experiment 1, adrenalectomy reduced the frequency of WDS following the administration of the 5-HT_2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) but had no effect on spontaneous WDS. In Experiment 2, chronic corticosterone treatment increased DOI-induced WDS in both adrenalectomized and sham-adrenalectomized rats. In Experiment 3, adrenalectomized and sham-adrenalectomized rats were compared on measures of spontaneous WDS and sexual behavior following the administration of estrogen alone, or estrogen in combination with progesterone. Chronic corticosterone and acute progesterone administration increased WDS and facilitated sexual receptivity and proceptivity, while adrenalectomy decreased WDS, facilitated sexual receptivity and inhibited proceptivity. These findings suggest that the behavioral effects seen following hypothalamic-pituitary-adrenal (HPA) axis disruption may, in part, be mediated by altered 5-HT_2A receptor responsivity.

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Short communicationBehavioural and biochemical evidence that glucocorticoids are not involved in DOI-elicited 5-HT2 receptor down-regulation

Abstract

Neurochem. Int.

Anal. Biochem.

Brain Res. Rev.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Anal. Biochem.

Brain Res.

Neuropharmacology

Withdrawal from chronic treatment with (±)-DOI causes super-sensitivity to 5-HT2 receptor-induced head-twitch behaviour in mice

Eur. J. Pharmacol.

Short communication
Behavioural and biochemical evidence that glucocorticoids are not involved in DOI-elicited 5-HT₂ receptor down-regulation

Withdrawal from chronic treatment with (±)-DOI causes super-sensitivity to 5-HT₂ receptor-induced head-twitch behaviour in mice