Raphe-Hippocampal Serotonin Neurotransmission In The Sex Related Differences of Adaptation to Stress: Focus on Serotonin-1A Receptor

Stress is the major predisposing and precipitating factor in the onset of depression which is the most significant mental health risk for women. Behavioral studies in animal models show that female sex though less affected by an acute stressor; exposure to repeated stressors induces coping deficits to impair adaptation in them. A decrease in the function of 5-hydroxytryptamine (5-HT; serotonin) in the hippocampus and an increased function of the 5-HT-1A receptor in the raphe nucleus coexist in depression. Pharmacological and neurochemical data are relevant that facilitation of serotonin neurotransmission via hippocampus due to desensitization of somatodendritic 5-HT1A receptors may lead to adaptation to stress. The present article reviews research on sex related differences of raphe-hippocampal serotonin neurotransmission to find a possible answer that may account for the sex differences of adaptation to stress reported in preclinical research and greater incidence of depression in women than men.     

Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.     

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

The serotonin 1A receptor (5-HT1A) has a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days (P) 14 to P30, with a maximal reduction of 40% at P21 and return to regular levels by P30. This developmental decrease in receptor levels has long-lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, post-natal knockdown of autoreceptors leads to long-term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from P14 to P21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders.     

Influence of AMPA/kainate receptors on extracellular 5-hydroxytryptamine in rat midbrain raphe and forebrain

1. The regulation of 5-hydroxytryptamine (5-HT) release by excitatory amino acid (EAA) receptors was examined by use of microdialysis in the CNS of freely behaving rats. Extracellular 5-HT was measured in the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), nucleus accumbens, hypothalamus, frontal cortex, dorsal and ventral hippocampus.
2. Local infusion of kainate produced increases in extracellular 5-HT in the DRN and MRN. Kainate infusion into forebrain sites had a less potent effect.
3. In further studies of the DRN and nucleus accumbens, kainate-induced increases in extracellular 5-HT were blocked by the EAA receptor antagonists, kynurenate and 6,7-dinitroquinoxaline-2,3-dione (DNQX).
4. The effect of infusing kainate into the DRN or nucleus accumbens was attenuated or abolished by tetrodotoxin (TTX), suggesting that the increase in extracellular 5-HT is dependent on 5-HT neuronal activity. In contrast, ibotenate-induced lesion of intrinsic neurones did not attenuate the effect of infusing kainate into the nucleus accumbens. Thus, the effect of kainate in the nucleus accumbens does not depend on intrinsic neurones.
5. Infusion of α-amino-3-hydroxy-5-methyl-4-isoxazolaproprionate (AMPA) into the DRN and nucleus accumbens induced nonsignificant changes in extracellular 5-HT. Cyclothiazide and diazoxide, which attenuate receptor desensitization, greatly enhanced the effect of AMPA on 5-HT in the DRN, but not in the nucleus accumbens.
6. In conclusion, AMPA/kainate receptors regulate 5-HT in the raphe and in forebrain sites.

     

Family-Based Study of AVPR1B Association and Interaction with Stressful Life Events on Depression and Anxiety in Suicide Attempts

The cortisol response to psychosocial stress may become dysregulated in stress-related disorders. It is potentiated by pituitary secretion of adrenocorticotropic hormone (ACTH), which is, in part, regulated by arginine vasopressin receptor-1B (AVPR1B). AVPR1B variants were previously reported to associate with mood and anxiety disorders. This study aims, for the first time, to investigate association of AVPR1B genetic variants with mood and anxiety outcomes in suicidal behavior.Using a family-based study design of 660 complete nuclear family trios with offspring who have made a suicide attempt (SA), we tested the direct association and linkage of AVPR1B single nucleotide polymorphisms (SNPs) with SA, as well as with depression and anxiety in SA. Main findings were the association and linkage of AVPR1B exon 1 SNP rs33990840 and a major 6-SNP haplotype representative of all common AVPR1B-SNPs, on the outcome of high Beck Depression Inventory scores in SA. By contrast, genetic associations with lifetime diagnoses of depression and anxiety in SA or gene–environment interactions between AVPR1B variants and stressful life events (SLEs) were not significant. An exploratory screen of interactions between AVPR1B and CRHR1 (corticotropin-releasing hormone receptor-1), the principal pituitary regulator of ACTH secretion, showed no support for gene–gene interactions on the studied outcomes. The results suggest that AVPR1B genetic variation, eg, non-synonymous SNP rs33990840 mediating putative consequences on ligand binding, has a role in SA etiology characterized by elevated depression symptoms, without involving AVPR1B-moderation of SLEs.     

The effect of the selective 5-HT1A agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain

1. We have examined the effects of the systemic administration of the selective 5-HT_1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated differentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus).
2. Alnespirone (0.1–3 mg kg⁻¹, s.c.) dose-dependently reduced extracellular 5-HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5-HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT_1A antagonist WAY-100635 (0.5 mg kg⁻¹, s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3 mg kg⁻¹, s.c.) in frontal cortex.
3. 8-OH-DPAT (0.025, 0.1 and 0.3 mg kg⁻¹, s.c.) also reduced extracellular 5-HT in a regionally-selective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1 mg kg⁻¹, s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nucleus at all doses examined.
4. Doses of both compounds close to their respective ED₅₀ values (0.3 mg kg⁻¹ alnespirone, 0.025 mg kg⁻¹ 8-OH-DPAT) reduced 5-HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8-OH-DPAT.
5. These data show that the reduction of 5-HT release elicited by alnespirone and 8-OH-DPAT is more important in forebrain areas innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by differences in the sensitivity of 5-HT_1A autoreceptors controlling 5-HT release, given the dissimilar effects of these two 5-HT_1A agonists in regions rich in cell bodies and nerve terminals. This suggests the presence of complex mechanisms of control of 5-HT release by 5-HT_1A receptors.

     

Concepts for the design of 5-HT1A serotonin agonists and antagonists

The accessibility and use of a standard 5-HT_1A agonist radioligand ([³H]8-hydroxy-2-(dipropylaminotetralin) has resulted in the availability of a large amount of binding data on various serotonergic agents. This, in turn, has permitted the formulation of structure—affinity relationships (SAFIR). By contrast, much less information is available concerning the agonist and antagonist activity of these agents. This is primarily due to a lack of standard evaluation procedures, controversy regarding the presynaptic versus postsynaptic nature of certain models, and the recent realization that many 5-HT_1A agents are partial agonists. Thus, it has been difficult to formulate structure—activity relationships (SAR) for these agents. The present review examines the various classes of 5-HT_1A serotonergic agents and the available data on their 5-HT_1A agonist and antagonist activity with the aim of formulating SAR. These SAR should provide useful information for the subsequent design of 5-HT_1A-selective agonists and antagonists. © 1992 Wiley-Liss, Inc.     

Occurrence of Alternaria and Other Toxins in Cereal Grains Intended for Animal Feeding Collected in Slovenia: A Three-Year Study

In recent years, the less-studied Alternaria mycotoxins have attracted increasing interest due to the lack of survey data and their ability to cause toxic effects in animals and humans. To fill the gap, the aim of this three-year survey was to investigate the presence and co-occurrence of Alternaria and other mycotoxins in a total of 433 cereal grain samples from Slovenian farms and agricultural cooperatives from 2014 to 2016. Using the multi-mycotoxin method, 14 mycotoxins were determined. In 53% of 433 analysed samples, contamination with at least one mycotoxin was found. Deoxynivalenol (DON) and tenuazonic acid (TeA) were present in 32% and 26% of cereal grain samples, respectively, whereas alternariol (AOH), tentoxin (TEN), alternariol monomethyl ether (AME), 3- and 15-acetyldeoxynivalenol (3- and 15-AcDON), and zearalenone (ZEN) were present in fewer than 15% of the samples. Ochratoxin A (OTA) was found in one rye sample, while diacetoxyscirpenol (DAS), HT-2 and T-2 toxin, and fumonisins B₁ and B₂ (FB1 and FB2) were not detected. The highest maximum and median concentrations of Alternaria toxins were determined in spelt in 2016 (TeA, 2277 µg/kg and 203 µg/kg, respectively), and those of Fusarium toxins in wheat in 2015 (DON, 4082 µg/kg and 387 µg/kg, respectively). The co-occurrence of two or more mycotoxins was found in 43% of the positive samples. The correlations between Alternaria toxins were very weak but statistically significant (r: 0.15–0.17, p: 0.0042–0.0165). A well-known correlation between Fusarium toxins DON and ZEN was weak and highly significant (r = 0.28, p < 0.0001).     

α1 Adrenoceptor subtypes: A synopsis of their pharmacology and molecular biology

Pharmacological and molecular biological studies have revealed heterogeneity among α₁ adrenoceptor subtypes. Pharmacological agents used to characterize these sites often possess only moderate selectivity for a particular α₁ adrenoceptor or have effects on other adrenergic or nonadrenergic receptors. Cloning studies have identified distinct amino acid sequences for three subtypes of α₁ adrenoceptor, although the pharmacological characteristics of expressed receptors did not always coincide with expectations. As a result, controversial and alternate classification concepts have emerged that propose different numbers of α₁ adrenoceptors or different naming conventions. Recent advances with an increasing variety of more selective compounds have resulted in an emerging consensus that identifies three subtypes of α₁ adrenoceptor. The pharmacological and molecular biological studies that have contributed to or promoted resolution of these controversies are discussed in this review. Drug Dev. Res. 39:54–107. © 1997 Wiley-Liss, Inc.     

Inhibition of the organic anion-transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment

AIM

To investigate the effect of quercetin on organic anion transporting polypeptide 1B1 (OATP1B1) activities in vitro and on the pharmacokinetics of pravastatin, a typical substrate for OATP1B1 in healthy Chinese-Han male subjects.

METHODS

Using human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1, we observed the effect of quercetin on OATP1B1-mediated uptake of estrone-3-sulphate (E3S) and pravastatin. The influence of quercetin on the pharmacokinetics of pravastatin was measured in 16 healthy Chinese-Han male volunteers receiving a single dose of pravastatin (40 mg orally) after co-administration of placebo or 500 mg quercetin capsules (once daily orally for 14 days).

RESULTS

Quercetin competitively inhibited OATP1B1-mediated E3S uptake with a K_i value of 17.9 ± 4.6 µm and also inhibited OATP1B1-mediated pravastatin uptake in a concentration dependent manner (IC₅₀, 15.9 ± 1.4 µm). In healthy Chinese-Han male subjects, quercetin increased the pravastatin area under the plasma concentration – time curve (AUC(0,10 h) and the peak plasma drug concentration (C_max) to 24% (95% CI 15, 32%, P < 0.001) and 31% (95% CI 20, 42%, P < 0.001), respectively. After administration of quercetin, the elimination half-life (t_1/2) of pravastatin was prolonged by 14% (95% CI 4, 24%, P = 0.027), with no change in the time to reach C_max (t_max). Moreover, quercetin decreased the apparent clearance (CL/F) of pravastatin by 18% (95% CI 75, 89%, P < 0.001).

CONCLUSIONS

These findings suggest that quercetin inhibits the OATP1B1-mediated transport of E3S and pravastatin in vitro and also has a modest inhibitory influence on the pharmacokinetics of pravastatin in healthy Chinese-Han male volunteers. The effects of quercetin on other OATP1B1 substrate drugs deserve further investigation.     

In vitro and in vivo Evaluation of CYP1A Interaction Potential of Terminalia Arjuna Bark

Terminalia arjuna Wight and Arn. (Combretaceae) is a tree having an extensive medicinal potential in cardiovascular disorders. Triterpenoids are mainly responsible for cardiovascular properties. Aqueous, hydroalcoholic and alcoholic extract of T. arjuna, arjunic acid and arjungenin were examined for their potential to inhibit CYP1A enzyme in rat and human liver microsomes. IC₅₀ values of aqueous, hydroalcoholic and alcoholic extract of T. arjuna was found to be 11.4, 28.9 and 44.6 μg/ml in rat liver microsomes while 30.0, 29.7 and 39.0 μg/ml in human liver microsomes, respectively for CYP1A. However IC₅₀ values of arjunic acid and arjungenin for both rat liver microsomes and human liver microsomes were found to be >50 μM. Arjunic acid and arjungenin did not show inhibition of CYP1A enzyme up to concentrations of 50 μM. These in vitro data indicate that Terminalia arjuna extracts contain constituents that can potently inhibit the activity of CYP1A, which could in turn lead to undesirable pharmacokinetic drug–herb interactions in vivo. Based on the in vitro data, interaction potential of the aqueous extract of Terminalia arjuna orally in rats was investigated. A probe substrate, phenacetin, was used to index the activity of CYP1A. In vivo pharmacokinetic study of coadministration of aqueous extract of Terminalia arjuna and phenacetin, revealed that the aqueous extract did not lead to any significant change in the pharmacokinetic parameters of phenacetin as compared with control group. Though there was no in vivo–in vitro correlation, drug interactions could arise with drugs having a narrow therapeutic range and extensively cleared by CYP1A enzyme, which could lead to undesirable side effects.     

Ibuprofen is a non-competitive inhibitor of the peptide transporter hPEPT1 (SLC15A1): possible interactions between hPEPT1 substrates and ibuprofen

BACKGROUND AND PURPOSE

Recently, we identified etodolac as a possible ligand for the human intestinal proton-couple peptide transporter (hPEPT1). This raised the possibility that other non-steroidal anti-inflammatory drugs, and especially ibuprofen, could also interact with hPEPT1. Here, we have assessed the interactions of ibuprofen with hPEPT1.

EXPERIMENTAL APPROACH

The uptake of [¹⁴C]Gly-Sar, [³H]Ibuprofen and other radio-labelled compounds were investigated in Madin–Darby canine kidney cells (MDCK)/hPEPT1, MDCK/Mock, LLC-PK₁ or Caco-2 cells. The transepithelial transport of ibuprofen and hPEPT1 substrates was investigated in Caco-2 cell monolayers.

KEY RESULTS

Ibuprofen concentration dependently inhibited hPEPT1-mediated uptake of Gly-Sar in MDCK/hPEPT1 cells (K_i^app= 0.4 mM) but uptake of ibuprofen in Caco-2 cells and MDCK/hPEPT1 cells was not inhibited by hPEPT1 substrates. The maximum uptake rate for Gly-Sar uptake was reduced from 522 pmol·min⁻¹·cm⁻² to 181 pmol·min⁻¹·cm⁻² and 78 pmol·min⁻¹·cm⁻² in the presence of 0.5 mM and 1 mM ibuprofen, respectively. The interaction between ibuprofen and hPEPT1 was thus non-competitive. In LLC-PK1 cells, ibuprofen (1 mM) did not influence the transporter-mediated uptake of glycine or α-methyl-D-glycopyranoside. In Caco-2 cell monolayers the absorptive transport of δ-aminolevulinic acid was reduced by 23% and 48% by ibuprofen (1 and 10 mM), respectively. Likewise the transport of Gly-Sar was reduced by 23% in the presence of ibuprofen (1 mM).

CONCLUSIONS AND IMPLICATIONS

Ibuprofen is a non-competitive inhibitor of hPEPT1. As ibuprofen reduced the transepithelial transport of δ-aminolevulinic acid, drug–drug interactions between ibuprofen and hPEPT1 drug substrates at their site of absorption are possible if administered together.     

Serotonin 1A Receptor Binding of [11C]CUMI-101 in Bipolar Depression Quantified Using Positron Emission Tomography: Relationship to Psychopathology and Antidepressant Response

BackgroundThe pathophysiology of bipolar disorder (BD) remains largely unknown despite it causing significant disability and suicide risk. Serotonin signaling may play a role in the pathophysiology, but direct evidence for this is lacking. Treatment of the depressed phase of the disorder is limited. Previous studies have indicated that positron emission tomography (PET) imaging of the serotonin 1A receptor (5HT1AR) may predict antidepressant response.MethodsA total of 20 participants with BD in a current major depressive episode and 16 healthy volunteers had PET imaging with [¹¹C]CUMI-101, employing a metabolite-corrected input function for quantification of binding potential to the 5HT1AR. Bipolar participants then received an open-labeled, 6-week clinical trial with a selective serotonin reuptake inhibitor (SSRI) in addition to their mood stabilizer. Clinical ratings were obtained at baseline and during SSRI treatment.ResultsPretreatment binding potential (BP_F) of [¹¹C]CUMI-101 was associated with a number of pretreatment clinical variables within BD participants. Within the raphe nucleus, it was inversely associated with the baseline Montgomery Åsberg Rating Scale (P = .026), the Beck Depression Inventory score (P = .0023), and the Buss Durkee Hostility Index (P = .0058), a measure of lifetime aggression. A secondary analysis found [¹¹C]CUMI-101 BP_F was higher in bipolar participants compared with healthy volunteers (P = .00275). [¹¹C]CUMI-101 BP_F did not differ between SSRI responders and non-responders (P = .907) to treatment and did not predict antidepressant response (P = .580). Voxel-wise analyses confirmed the results obtained in regions of interest analyses.ConclusionsA disturbance of serotonin system function is associated with both the diagnosis of BD and its severity of depression. Pretreatment 5HT1AR binding did not predict SSRI antidepressant outcome.The study was listed on clinicaltrials.gov with identifier {"type":"clinical-trial","attrs":{"text":"NCT02473250","term_id":"NCT02473250"}}NCT02473250.     

Characterization of 4-(2-hydroxyphenyl)-1-[2'-[N-(2'-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-DMPPF) as a new potent 5-HT1A antagonist

BACKGROUND AND PURPOSE: The identification of potent and selective radioligands for the mapping of 5-HT receptors is interesting both for clinical and experimental research. The aim of this study was to compare the potency of a new putative 5-HT(1A) receptor antagonist, p-DMPPF, (4-(2-hydroxyphenyl)-1-[2'-[N-(2'-pyridinyl)-p-fluorobenzamido]ethyl]piperazine) with that of the well-known 5-HT(1A) antagonists, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide) and its fluorobenzoyl analogue, p-MPPF (4-(2-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-p-fluorobenzamido]ethyl]piperazine). EXPERIMENTAL APPROACH: Single cell extracellular recordings of dorsal raphe (DR) neurones were performed in rat brain slices. The potency of each compound at antagonizing the effect of the 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)-tetraline], was quantified using the Schild equation. The pharmacological profile of p-DMPPF was defined using competition binding assays. KEY RESULTS: Consistently with a 5-HT(1A) receptor antagonist profile, incubation of slices with an equimolar (10 nM) concentration of each compound markedly reduced the inhibitory effect of 8-OH-DPAT on the firing rate of DR neurones, causing a significant rightward shift in its concentration-response curve. The rank order of potency of the antagonists was WAY-100635>p-DMPPF>or=p-MPPF. The sensitivity of DR neurones to the inhibitory effect of 8-OH-DPAT was found to be heterogeneous. The binding experiments demonstrated that p-DMPPF is highly selective for 5-HT(1A) receptors, with a K(i) value of 7 nM on these receptors. CONCLUSIONS AND IMPLICATIONS: The potency of the new compound, p-DMPPF, as a 5-HT(1A) antagonist is similar to that of p-MPPF in our electrophysiological assay. Its selectivity towards 5-HT(1A) receptors makes it a good candidate for clinical development.     

Carry-Over of Zearalenone and Its Metabolites to Intestinal Tissues and the Expression of CYP1A1 and GSTπ1 in the Colon of Gilts before Puberty

The objective of this study was to evaluate whether low doses of zearalenone (ZEN) affect the carry-over of ZEN and its metabolites to intestinal tissues and the expression of CYP1A1 and GSTπ1 in the large intestine. Prepubertal gilts (with a BW of up to 14.5 kg) were exposed in group ZEN to daily ZEN5 doses of 5 μg/kg BW (n = 15); in group ZEN10, 10 μg/kg BW (n = 15); in group ZEN15, 15 μg/kg BW (n = 15); or were administered a placebo (group C, n = 15) throughout the experiment. After euthanasia, tissues were sampled on exposure days 7, 21, and 42 (D1, D2, and D3, respectively). The results confirmed that the administered ZEN doses (LOAEL, NOAEL, and MABEL) were appropriate to reliably assess the carry-over of ZEN. Based on the observations made during 42 days of exposure to pure ZEN, it can be hypothesized that all mycotoxins (ZEN, α-zearalenol, and β-zearalenol) contribute to a balance between intestinal cells and the expression of selected genes encoding enzymes that participate in biotransformation processes in the large intestine; modulate feminization processes in prepubertal gilts; and elicit flexible, adaptive responses of the macroorganism to mycotoxin exposure at the analyzed doses.     

Electrophysiology of 5-HT1A receptors in the rat hippocampus and cortex

Electrophysiological recordings from hippocampus and cortex have demonstrated that one of the most prominent effects of serotonin in these regions is a membrane hyperpolarization that effectively inhibits neuronal activity. The use of the in vitro brain slice preparation has allowed for detailed pharmacological and physiological studies of this response. Pharmacological analysis using agonists and antagonists indicates that these responses are mediated by activation of receptors of the 5-HT_1A subtype. Buspirone, ipsapirone and 8-OHDPAT are all partial agonists at this receptor with 8-OHDPAT exhibiting an intrinsic activity approximately one-fourth that of serotonin. The ability of 5-HT_1A receptor agonists to elicit a hyperpolarization is dependent on intracellular GTP, suggesting the involvement of a G protein in the transmembrane signalling mechanism. In agreement with this idea, injection of the stable GTP analog GTPγS renders the serotonin induced hyperpolarization irreversible, while GDPβS blunts its effects and pertussis toxin pretreatment blocks it. The 5-HT_1A receptor induced hyperpolarization is mediated by an increase in potassium conductance. While the identity of the potassium channel remains to be determined, its basic characteristics identify it as belonging to a general class of inwardly rectifying G protein activated potassium channels ubiquitously distributed in neuronal and cardiac muscle tissues. In the rat hippocampus and cortex, most pyramidal cells co-express 5-HT_1A with either 5-HT₄ or 5-HT₂ receptors, respectively, which in turn act to increase the ability of strong stimuli to excite these cells. As a result the net effect of serotonin on membrane excitability is dependent on the strength of incoming stimuli. Weak stimuli are depressed by the coactivation of these receptor subtypes while strong stimuli are enhanced. Thus the effects of selective 5-HT_1A ligands are likely to depend not only on their direct effect on membrane excitability but also on how they alter ongoing serotonergic neurotransmission. © 1992 Wiley-Liss, Inc.     

Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population

AIMS

To evaluate sodium channel genes as candidates for epilepsy susceptibility and their role in therapeutic efficacy, we screened coding single-nucleotide polymorphism of SCN1A p. Thr 1067 Ala or c.3184 A→G (rs2298771) and SCN2A p.Arg19Lys or c.56 G→A (rs17183814) in north Indian epilepsy patients.

METHODS

The genotyping was performed in 160 control subjects and 336 patients with epilepsy, of whom 117 were drug resistant and 219 were drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital and valproate was also performed in 20% of the patients to confirm compliance.

RESULTS

AG genotype of SCN1A 3184 A→G polymorphism was significantly higher and associated in epilepsy patients [P= 0.005; odds ratio (OR) 1.76, 95% confidence interval (CI) 1.19, 2.61], whereas A variant of SCN2A c.56 G→A was associated with multiple drug resistance in north Indian patients with epilepsy (P= 0.03; OR 1.62, 95% CI 1.03, 2.56).

CONCLUSIONS

Overall, results indicate a differential role of genetic polymorphisms of sodium channels SCN1A and SCN2A in epilepsy susceptibility and drug response.     

SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor

相似文献   

Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors

Background and purpose:

{"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599, a novel 5-hydroxytryptamine (5-HT)_1A receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 at somatodendritic autoreceptors and postsynaptic 5-HT_1A heteroreceptors.

Experimental approach:

In vivo single unit and local field potential recordings and microdialysis in the rat.

Key results:

{"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 µg·kg⁻¹ i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 µg·kg⁻¹ i.v.). Both effects were reversed by the 5-HT_1A antagonist (±)WAY100635. {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT_1A receptors) with an ED₅₀ of 30 µg·kg⁻¹ i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT_1A autoreceptor activation) with an ED₅₀ of 240 µg·kg⁻¹ i.p. Likewise, application of {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 were prevented by administration of (±)WAY100635.

Conclusions and implications:

These results indicate that systemic administration of {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 preferentially activates postsynaptic 5-HT_1A receptors in PFC rather than somatodendritic 5-HT_1A autoreceptors. This regional selectivity distinguishes {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 from previously developed 5-HT_1A receptor agonists, which preferentially activate somatodendritic 5-HT_1A autoreceptors, suggesting that {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.