Developmental regulation of 5-HT2 and 5-HT1c mRNA and receptor levels

We investigated the regulation of 5-HT2 and 5-HT1c receptors and their corresponding mRNAs during rat brain development. This study showed that 5-HT2 and 5-HT1c receptors increased markedly during ontogeny. 5-HT2 receptors, measured with [3H]ketanserin or [125I]lysergic acid diethylamide binding, increased 8-fold between embryonic day 17 (E17) and postnatal day 13 (P13). 5-HT2 receptor mRNA levels, quantified by probing Northern blots of total RNA with a synthetic oligonucleotide cDNA probe, multiplied 13-fold between E17 and P5. The developmental pattern of 5-HT2 receptor and mRNA expression appeared to correlate with the serotonergic hyperinnervation of the cortex which occurs between P2 and P17. 5-HT1c receptors, measured with [125I]lysergic acid diethylamide under site-specific conditions, increased 2-fold between E17 and P27, 5-HT1c mRNA increased 5-fold between E17 and P27. Interestingly, the developmentally induced variations in 5-HT1c receptors did not precisely correlate with mRNA alterations. Further study of the factors responsible for these alterations could help to explain the molecular and biochemical mechanisms responsible for modulating receptor levels in vivo.     

Detection of the 5-HT1A receptor and 5-HT1A receptor mRNA in the rat bowel and pancreas: Comparison with 5-HT1Preceptors

We tested the hypothesis that the rat bowel and pancreas contain 5-HT_1A receptors. ₃H-8-hydroxy-2-(di-n-propylamino) tetralin (₃H-8-OH-DPAT) was used as a radioligand. Binding of ₃H-8-OH-DPAT to membranes derived from the myenteric plexus and the pancreas was investigated by rapid filtration. Alternatively, radioautography was employed to locate ₃H-8-OH-DPAT binding sites in frozen sections of unfixed bowel or pancreas. An excess of 5-HT (10 μM) was used to define nonspecific binding. Saturable, high affinity binding of ₃H-8-OH-DPAT to enteric (K_d= 2.8 ± 1.1 nM; B_max =83.8 ± 4.3 fmol/mgproteim) and pancreatic (K_d = 6.6 ± 1.3 nM; B_max = 44 ± 2.2 fmol/mg protein) membranes was found. The binding of ₃H-8-OH-DPAT to enteric and pancreatic membranes was inhibited by 8-OH-DPAT, NAN-190, and spiperone. In contrast, the binding of ₃H-8-OH-DPAT to enteric and pancreatic membranes was not inhibited by 5-carboxyamidotryptamine, or by avariety of compounds known to bind to other subtypes of 5-HT receptor. Digoxigenin-labeled oligonucleotides were found to detect mRNA encoding the 5-HT_1A receptor in a subset of neurons in myenteric and submucosal ganglia. In contrast, 5-HT_1A mRNA was not found in the pancreas. Radioautography revealed that the highest density of ₃H-8-OH-DPAT binding sites was found in the stomach. These sites were especially numerous in the lamina propria adjacent to gastric glands, and in myenteric ganglia. Pancreatic 5-HT_1Areceptors were located on nerves, lymphoid tissue (especially the capsule of nodes), and on cells scattered in the pancreatic parenchyma. The concentration of ₃H-8-OH-DPAT binding sites in the rat bowel and pancreas was less than that of ₃H-5-HT binding sites; however, the distribution of ₃H-8-OH-DPAT binding sites was similar to that of sites that bind ₃H-5-HT. It is concluded that the rat gut and its extension in the pancreas contains 5-HT_1A receptors. Many, if not all, of the nerve cells and processes that express 5-HT_1A receptors express 5-HT_1p receptors as well. The function of these receptors in the physiology of the entero-pancreatic innervation remains to be determined. © 1993 Wiley-Liss, Inc.     

Repeated antenatal glucocorticoid treatment decreases hypothalamic corticotropin releasing hormone mRNA but not corticosteroid receptor mRNA expression in the fetal guinea-pig brain

Approximately 10% of pregnant women are treated with synthetic glucocorticoids in late gestation, to promote fetal lung maturation. The effectiveness of this treatment has led to the use of repeated dose regimens, with little knowledge of the impact on neuroendocrine development. Animal studies have recently shown that repeated fetal glucocorticoid exposure can lead to permanent changes in hypothalamic-pituitary-adrenal (HPA) function in offspring. In this study, we hypothesized that such treatment modifies corticotropin releasing hormone (CRH), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) systems in the developing limbic system and hypothalamus. Pregnant guinea-pigs were treated with dexamethasone, betamethasone or vehicle on days 40,41,50,51,60 and 61 of gestation (birth = 68 days). On day 62, guinea-pigs were killed and the fetuses rapidly removed. Glucocorticoid treatment resulted in a dose-dependent reduction in plasma cortisol concentrations in both male and female fetuses. There was also a significant reduction in CRH mRNA expression in the hypothalamic paraventricular nucleus. In contrast, exposure to glucocorticoid increased MR mRNA expression in the hippocampus (CA1/2 and CA3) and dentate gyrus of female fetuses. There was a small but significant increase in GR mRNA expression in limbic structures in male fetuses following treatment with 1 mg/kg dexamethasone. However, there was no significant effect of glucocorticoid exposure on hippocampal GR mRNA expression in female fetuses, or hypothalamic GR mRNA in either males or females. In conclusion, repeated maternal glucocorticoid treatment inhibits fetal HPA function. The fact that CRH mRNA levels were reduced indicates that synthetic glucocorticoids enter the fetal brain. By contrast, fetal glucocorticoid exposure does not downregulate GR mRNA, and increases MR mRNA expression. The latter likely reflects removal of circulating endogenous ligand (cortisol). These alterations may form the basis for permanently modified HPA activity in later life.     

The development of the glucocorticoid receptor system in the rat limbic brain. III. Negative-feedback regulation

In the neonatal rat, there are parallel increases with age in the concentrations of glucocorticoid receptors in the limbic system, and in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to negative-feedback inhibition by circulating glucocorticoids. We speculated that the increasing receptor concentrations may mediate this increasing sensitivity of the HPA axis to the suppressive effects of glucocorticoids. To examine this idea we treated rats with exogenous corticosterone from days 29 to 34, resulting in a down-regulation of glucocorticoid receptors in the brain at Day 35 to levels similar to those of younger animals. Subjects whose maturational increase in receptors was reversed in this manner were less sensitive to feedback inhibition of glucocorticoids. Specifically, compared to controls they continued to secrete corticosterone after the end of stress, and were relatively insensitive to the suppressive effects of the synthetic glucocorticoid, dexamethasone, on corticosterone titers. Our data specifically implicate the hippocampus in modulating feedback sensitivity, as down-regulation was extensive in this structure, and did not occur in the septum, amygdala, hypothalamus or pituitary.     

Reduction in 5-HT1A receptor density, 5-HT1A mRNA expression, and functional correlates for 5-HT1A receptors in genetically defined aggressive rats

The present experiments tested the hypothesis that one of the critical mechanisms underlying genetically defined aggressiveness involves brain serotonin 5-HT1A receptors. 5-HT1A receptor density, the receptor mRNA expression in brain structures, and functional correlates for 5-HT1A receptors identified as 8-OH-DPAT-induced hypothermia and lower lip retraction (LLR) were studied in Norway rats bred for 59 generations for the lack of aggressiveness and for high affective aggressiveness with respect to man. Considerable differences between the highly aggressive and the nonaggressive rats were shown in all three traits. A significant decrease in B(max) of specific receptor binding of [3H]8-OH-DPAT in the frontal cortex, hypothalamus, and amygdala and a reduction in 5-HT1A receptor mRNA expression in the midbrain of aggressive rats were found. 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and did not affect significantly the body temperature in aggressive rats. Similar differences were revealed in 8-OH-DPAT-induced LLR: LLR was expressed much more in nonaggressive than in aggressive animals. Additionally, 8-OH-DPAT (0.5 mg/kg i.p.) treatment significantly attenuated the aggressive response to man. The results demonstrated an association of aggressiveness with reduced 5-HT1A receptor expression and function, thereby providing support for the view favoring the idea that brain HT1A receptor contributes to the genetically defined individual differences in aggressiveness.     

Corticosteroids regulate 5-HT(1A) but not 5-HT(1B) receptor mRNA in rat hippocampus

The role of mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) in the regulation of serotonin receptors has not been clearly delineated. There is no consensus regarding the regulation of 5-HT(1A) receptors, and corticosteroid regulation of 5-HT(1B) mRNA has not been previously studied. We compared the effects of long-term (two week) adrenalectomy (no MR or GR activation) and several hormone replacement protocols designed to stimulate MR selectively (ALDO), MR and GR (HCT), and continuous MR with cyclical GR activation (SHAM adrenalectomy). 5-HT(1A) and 5-HT(1B) mRNAs were measured by in situ hybridization in hippocampus and raphe nuclei. None of the experimental manipulations altered 5-HT(1B) mRNA levels in the hippocampus or dorsal raphe, and also had no effect on 5-HT(1A) mRNA in dorsal or median raphe. However, 5-HT(1A) mRNA levels were regulated in a complex manner in the different subfields of hippocampus. We conclude that both MR and GR play an integrated role in regulating 5-HT(1A) mRNA levels in hippocampus while having no effect on 5-HT(1B) mRNA levels under these conditions.     

Development of 5-HT1A receptor radioligands to determine receptor density and changes in endogenous 5-HT

[(18)F]FCWAY and [(18)F]FPWAY, analogues of the high affinity 5-HT(1A) receptor (5-HT(1A)R) antagonist WAY100635, were evaluated in rodents as potential radiopharmaceuticals for determining 5-HT(1A)R density and changes in receptor occupancy due to changes in endogenous serotonin (5-HT) levels. The in vivo hippocampus specific binding ratio [(hippocampus(uptake)/cerebellum(uptake))-1] of [(18)F]FPWAY was decreased to 32% of the ratio of [(18)F]FCWAY, indicating that [(18)F]FPWAY has lower affinity than [(18)F]FCWAY. The 5-HT(1A)R selectivity of [(18)F]FPWAY was confirmed using ex vivo autoradiography studies with 5-HT(1A)R knockout, heterozygous, and wildtype mice.Pre- or post-treatment of awake rodents in tissue dissection studies with paroxetine had no effect on hippocampal binding of [(18)F]FCWAY or [(18)F]FPWAY compared to controls, indicating neither tracer was sensitive to changes in endogenous 5-HT. In mouse ex vivo autoradiography studies in which awake mice were treated with fenfluramine following the [(18)F]FPWAY, a significant decrease was not observed in the hippocampus specific binding ratios. In rat dissection studies with fenfluramine administered following [(18)F]FPWAY or [(18)F]FBWAY ([(18)F]-MPPF) in awake or urethane-anesthetized rats, no significant differences in the specific binding ratios of the hippocampus were observed compared to their respective controls. [(18)F]FPWAY and [(18)F]FBWAY uptakes in all brain regions were increased variably in the anesthetized group (with the greatest increase in the hippocampus) vs. the awake group, but were decreased in the fenfluramine-treated anesthetized group vs. the anesthetized group. These data are best explained by changes in blood flow caused by urethane and fenfluramine, which varies from region to region in the brain.     

Regional expression of 5-HT1B receptor mRNA in the human brain

The regional mRNA expression pattern of 5-HT(1B) receptors has been extensively characterized in the rodent and guinea pig brain, but a detailed mapping of the 5-HT(1B) receptor mRNA expression in the human brain has not previously been performed. In the present study, the mRNA expression of 5-HT(1B) receptors was analyzed using in situ hybridization histochemistry and whole hemisphere sections of the human postmortem brain. The mRNA expression was compared with the autoradiographic distribution of 5-HT(1B) receptors. High levels of mRNA expression were found in the striatum, cortex, lateral geniculate nucleus, and raphe nuclei. The expression was higher in ventral than in dorsal striatal regions and was absent from the substantia nigra and pallidum, where high levels of 5-HT(1B) receptors were found. A layer-specific expression pattern was observed in cortical regions. The results extend previous knowledge about the localization of the 5-HT(1B) receptor in the human brain. This study provides evidence of a mismatch of the regional expression of 5-HT(1B) receptor mRNA and the 5-HT(1B) receptor distribution in human brain, similar to what has been demonstrated in other species. This is in line with the localization of this receptor subtype in nerve terminals. The results give support to species differences in the cortical mRNA expression pattern of this receptor subtype.     

Wheel running alters serotonin (5-HT) transporter, 5-HT1A, 5-HT1B, and alpha 1b-adrenergic receptor mRNA in the rat raphe nuclei.

BACKGROUND: Altered serotonergic (5-HT) neurotransmission is implicated in the antidepressant and anxiolytic properties of physical activity. In the current study, we investigated whether physical activity alters factors involved in the regulation of central 5-HT neural activity. METHODS: In situ hybridization was used to quantify levels of 5-HT transporter (5-HTT), 5-HT(1A), 5-HT(1B), and alpha(1b)-adrenergic receptor (alpha(1b) ADR) messenger ribonucleic acids (mRNAs) in the dorsal (DRN) and median raphe (MR) nuclei of male Fischer rats after either sedentary housing or 3 days, 3 weeks, or 6 weeks of wheel running. RESULTS: Wheel running produced a rapid and lasting reduction of 5-HT(1B) mRNA in the ventral DRN. Three weeks of wheel running decreased 5-HTT mRNA in the DRN and MR and increased alpha(1b) ADR mRNA in the DRN. After 6 weeks of wheel running, 5-HTT mRNA remained reduced, but alpha(1b) ADR mRNA returned to sedentary levels. Serotonin(1A) mRNA was increased in the MR and certain DRN subregions after 6 weeks only. CONCLUSIONS: Data suggest that the central 5-HT system is sensitive to wheel running in a time-dependent manner. The observed changes in mRNA regulation in a subset of raphe nuclei might contribute to the stress resistance produced by wheel running and the antidepressant and anxiolytic effects of physical activity.     

Comparative anatomical distribution of 5-HT1A receptor mRNA and 5-HT1A binding in rat brain--a combined in situ hybridisation/in vitro receptor autoradiographic study.

The present study examined the comparative distribution of 5-HT1A receptor mRNA and 5-HT1A receptors in rat brain using a combination of in situ hybridisation histochemistry and in vitro receptor autoradiography. 5-HT1A mRNA was visualized using a 910 bp cRNA probe synthesised from a BalI-PvuII fragment of the rat 5-HT1A reetor gene, while 5-HT1A receptors were labelled with the 5-HT1A-selective ligand 8-OH-DPAT. In general terms, there was a complementary distribution of cells expressing 5-HT1A receptor mRNA and 5-HT1A receptor sites. High levels of both 5-HT1A mRNA and 5-HT1A receptors were evident in the hippocampal formation (CA1, CA3, dentate gyrus), entorhinal cortex, and raphe nuclei and lower levels in neocortex and thalamus. Although 5-HT1A mRNA was not expressed in any regions which did not also exhibit 5-HT1A receptors, within both the diagonal band and the medial septal nucleus mRNA levels were proportionately higher than 5-HT1A receptor levels, possibly reflecting receptor transport or a heterogeneity in 5-HT1A receptor turnover mechanisms. 5-HT1A receptor mRNA and 5-HT1A binding sites were undetectable in caudate/putamen and cerebellar regions. The present data indicate the synthesis of 5-HT1A receptors both in raphe serotonergic cells and anatomically specific serotonergic projection areas, further supporting both a presynaptic autoregulatory and postsynaptic modulatory role for this receptor in serotonergic transmission.     

Influence of escitalopram treatment on 5-HT 1A receptor binding in limbic regions in patients with anxiety disorders

There is an increasing interest in the underlying mechanisms of the antidepressant and anxiolytic treatment effect associated with changes in serotonergic neurotransmission after treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) in humans. The 5-HT(1A) receptor is known to play a crucial role in the pathophysiology of affective disorders, and altered 5-HT(1A) receptor binding has been found in anxiety patients. SSRI treatment raises the 5-HT level in the synaptic cleft and might change postsynaptic receptor densities. Therefore, our study in patients suffering from anxiety disorders investigated the effects of long-term treatment with escitalopram on the 5-HT(1A) receptor. A longitudinal positrone emission tomography (PET) study in 12 patients suffering from anxiety disorders was conducted. Two dynamic PET scans were performed applying the selective 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635. Eight regions of interest were defined a priori (orbitofrontal cortex, amygdala, hippocampus, subgenual cortex, anterior and posterior cingulate cortex, dorsal raphe nucleus and cerebellum as reference). After the baseline PET scan, patients were administered escitalopram (average dose of 11.2+/-6.0 mg day(-1)) for a minimum of 12 weeks. A second PET scan was conducted after 109+/-27 days. 5-HT(1A) receptor binding potentials in 12 patients were assessed by PET applying the Simplified Reference Tissue Model.There was a significant reduction in the 5-HT(1A) receptor binding potential after a minimum of 12 weeks of escitalopram treatment in the hippocampus (P=0.006), subgenual cortex (P=0.017) and posterior cingulate cortex (P=0.034). The significance of the hippocampus region survived the Bonferroni-adjusted threshold for multiple comparisons. These PET data in humans in vivo demonstrate a reduction of the 5-HT(1A) binding potential after SSRI treatment.     

Corticosterone regulation of serotonin transporter and 5-HT1A receptor expression in the aging brain

Hypercortisolemia is often observed in patients suffering from major depression. As the serotonergic (5-hydroxytryptamine; 5-HT) system plays a major role in the etiology of depression, a loss of endocrine and neurotransmitter system interactions, including corticosterone regulation of 5-HT transporter (5-HTT) and 5-HT receptor expression, may underlie age-related deficits in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and correlate with an increased incidence of depression with advancing age. In this study, female Fischer 344 rats, ages 3, 13, and 18 months, were bilaterally adrenalectomized and supplemented for 3 weeks with corticosterone (0, 200, or 600 mg; LC, MC, or HC, respectively) containing 21 day sustained-release pellets implanted subcutaneously. Quantitative autoradiography of hippocampal and cortical regions using [3H]citalopram revealed a significant decrease in hippocampal 5-HTT binding in the 3-month HC treatment group compared to age-matched MC and LC groups; this loss was not present in the 13- or 18-month groups. Similarly, quantitative autoradiography using the radiolabeled 5-HT(1A) receptor agonist 8-hydroxy-2-(di-N-propylamino) tetralin demonstrated a significant decline in receptor density in 3- and 13-month MC and HC groups as compared to age-matched LC groups in the hippocampus. These hormone treatments (MC or HC), however, failed to alter hippocampal 5-HT(1A) binding site density in the 18-month groups as compared to the age-matched LC group. The 5-HT(2A) receptor was also evaluated using [3H]ketanserin and showed no age- or corticosterone-related changes in the cortex. Overall, an age-associated deficit in the regulation of the hippocampal serotonergic system by varied corticosterone treatment was revealed in the present study, which may underlie the increased incidence of depression and hypercortisolemia found with advancing age.     

Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain

Summary. Radioligand binding studies were done to investigate the effect of chronic administration of fluoxetine on 5-HT₁ receptor mediated response to adenylate cyclase (AC) in rat brain. Our studies revealed a significant decrease in the densities of 5-HT₁ and 5-HT_1A receptor sites in cortex and hippocampus of rat brain after chronic administration of fluoxetine (10 mg/Kg body wt.). However there was no significant change in the affinity of [³H]5-HT and [³H]DPAT for 5-HT₁ and 5-HT_1A receptor sites, respectively. However, in striatum, along with a significant (75%) downregulation of 5-HT₁ sites, the affinity of [³H]5-HT to these sites was increased, as revealed by decrease in Kd (0.50 ± 0.08 nM). Displacement studies showed that fluoxetine has higher affinity for 5-HT_1A receptors with a Ki value of 14.0 ± 2.8 nM, than 5-HT₁ sites. No significant change was observed in basal AC activity in any region after fluoxetine exposure. However, in cortex of experimental rats the 5-HT stimulated AC activity was significantly increased (16.03 ± 0.97 pmoles/mg protein; p < 0.01), when compared to 5-HT stimulated AC activity (12.98 ± 0.78 pmoles/mg protein) in control rats. The increase in 5-HT stimulated AC activity in cortex may be due to the significant downregulation of 5-HT_1A sites in cortex after fluoxetine exposure as these sites are negatively coupled to AC. The observed significant decrease in 5-HT₁ sites with concomitant increase in 5-HT stimulated AC activity, after fluoxetine treatment, suggests that fluoxetine, which has high affinity for these sites, acts by modulating the 5-HT_1A receptor mediated response in brain. Accepted August 25, 1999     

Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia.

BACKGROUND: Alterations of serotonin neurotransmission are implicated in both mood disorders and schizophrenia. Specific serotonin-receptor-based abnormalities in these psychiatric illnesses have been intensively studied; however, it has been difficult to draw any conclusions because of a lack of consensus. These inconsistencies have most likely arisen from the unavailability of selective ligands. METHODS: Our study used in situ hybridization to quantify 5-HT(1A), 5-HT(1B), and 5-HT(2A) mRNA levels in the hippocampus (HC) and 5-HT(1A) and 5-HT(2A) mRNA levels in the dorsolateral prefrontal cortex (DLPFC) of subjects with a history of major depression disorder (MDD), bipolar disorder (BPD), schizophrenia, and a normal comparison group (15 subjects per group). RESULTS: In the DLPFC, there is a significant decrease in 5-HT(1A) mRNA of subjects with MDD and in 5-HT(2A) mRNA of subjects with BPD. Subjects with MDD have a significant decrease in 5-HT(1A) mRNA in the HC; subjects with BPD and schizophrenia had increased 5-HT(1B) mRNA levels and a significant decrease in 5-HT(2A) mRNA levels in the hippocampal formation. CONCLUSIONS: Alterations in 5-HT(1A,) 5-HT(1B), and 5-HT(2A) mRNA levels in the brains of subjects with both mood disorders and schizophrenia add further support for hypothesis of dysregulation of the serotonergic system in these psychiatric disorders.     

Environmental enrichment selectively increases 5-HT1A receptor mRNA expression and binding in the rat hippocampus

Environmental enrichment augments neuronal plasticity and cognitive function and possible mediators of these changes are of considerable interest. In this study, male rats were exposed to environmental enrichment or single housing for 30 days. Rats from the enriched group had significantly higher 5-HT1A receptor mRNA expression in the dorsal hippocampus (62%, 59% and 44% increase in the CA1, CA2 and CA3 subfields, respectively). This was associated with significantly higher [³H]8-OH-DPAT binding in the inferior part of CA1. No changes were seen for 5-HT2A or 5-HT2C receptor mRNAs. The neuronal plasticity detected after environmental change may be mediated, in part, through 5-HT1A receptors.     

Prolonged 5-HT1A/5-HT2A receptor cross-talk is absent prior to adulthood in rats

In adult rats, serotonin 1A (5-HT1A) receptor activation produces heterologous desensitization of serotonin 2A (5-HT2A) neuroendocrine function at 1 h that persists up to 72 h. This study determined whether prolonged 5-HT1A/5-HT2A cross-talk exists before sexual maturation. Adolescent male rats (postnatal day 39) received an injection with saline or (+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide [(+)8-OH-DPAT] 24 h before receiving a challenge injection of saline, (+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, or (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl [(-)DOI] o assess changes in basal, 5-HT1A, and 5-HT2A receptor-mediated hormone responses. Although homologous desensitization of 5-HT1A neuroendocrine responses was present at 24 h, heterologous desensitization of 5-HT2A neuroendocrine responses was not. These data suggest that 5-HT1A heterologous desensitization of 5-HT2A receptor function does not develop until adulthood, is more transient, or follows a different time course before maturation.     

西酞普兰对脑卒中后抑郁大鼠海马齿状回5-羟色胺1A受体表达的影响

目的 观察西酞普兰对拟脑卒中后抑郁(post-stroke depression,PSD)大鼠海马齿状回5-羟色胺1A(5-HT1A)受体表达的影响,探讨其治疗PSD可能的药理机制.方法 将雄性SD大鼠分为3组正常对照组、拟PSD组和西酞普兰干预组.左侧大脑中动脉阻塞(MCAO)联合慢性不可预见温和应激刺激(CMS)及孤养法建立拟PSD动物模型,同时予西酞普兰(10 mg·kg-1·day-1)干预4周,荧光实时定量PCR和Western印迹方法检测并比较CMS开始后第19、28天各组大鼠海马齿状回5-HT1A受体的基因(mRNA表达水平)和蛋白表达水平.结果 CMS开始后第19天,西酞普兰组5-HT1A受体的基因和蛋白表达均高于拟PSD组[(0.131±0.008)vs(0.012±0.001)和(0.95±0.06)vs(0.40±0.03),P均小于0.001].第28天,西酞普兰组5-HT1A受体的基因和蛋白表达均高于拟PSD组[(0.224±0.012)vs(0.013±0.001)和(0.52±0.06)vs(0.08±0.02),P均小于0.001].结论 西酞普兰促进拟PSD大鼠海马齿状回5-HT1A受体的基因和蛋白表达,从而可促进海马神经重塑,这可能为西酞普兰治疗PSD的分子机制之一.     

Central 5-HT(1) and 5-HT(2) binding sites in transgenic mice with reduced glucocorticoid receptor number

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-HT(2) 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 CA(3) 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-HT(2) 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 CA(2) area (+29.2+/-11.3%). The observed differences in binding to 5-HT(1) and 5-HT(2) 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.