Serotonin and hallucinogens

This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as partial agonists at 5-HT 2A and other 5-HT 2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HT The accidental discovery in 1943 of the hallucinogenic properties of the synthetic ergoline compound LSD (dlysergic acid diethylamide) by the chemist Albert Hoffman is well known. Five years later, in 1948, serotonin (later determined to be 5-hydroxytryptamine or 5-HT) was found in bovine blood serum NEURONAL ACTIONS OF HALLUCINOGENIC DRUGS Effects of Hallucinogens on 5-HT Neurons of the Raphe Nuclei The identification of 5-HT as a neurotransmitter was not achieved until the mid-1960s, when monoaminergic neuronal pathways in the brain were discovered and mapped by histochemical fluorescence methods (Dähl-strom and Fuxe 1964). These maps, which revealed that 5-HT neuronal cell bodies were clustered in the raphe nuclei of the brainstem, provided the basis for singlecell electrophysiological recordings from identified 5-HT neurons. LSD was found to have a potent inhibitory effect upon the tonically firing 5-HT neurons of the dorsal raphe nucleus In subsequent years, the delineation of multiple 5-HT receptor subtypes by radiolabeled ligand binding and molecular methods (see Affinity for 5-HT 2 Receptors Correlates with Hallucinogenic Potency Glennon, Titeler, and their colleagues showed that there is an excellent correlation between the affinity of both indoleamine and phenethylamine hallucinogens for 5-HT 2 receptors and hallucinogenic potency in humans Actions at 5-HT 2C receptors, which have been associated with anxiogenic responses Hallucinogens Enhance Sensory Responses in the Locus Coeruleus via 5-HT 2A Receptors The locus coeruleus (LC) consists of two dense clusters of noradrenergic neurons located bilaterally in the upper pons at the lateral border of the 4th ventricle. The LC, which projects diffusely to virtually all regions of the neuraxis, receives an extraordinary convergence of somatic, visceral, and other sensory inputs from all regions of the body, has been likened to a novelty detector for salient external stimuli (Aston-Jones and Bloom 1981; Cedarbaum and Aghajanian 1978). In this context, it is of interest that the systemic administration of LSD, mescaline, or other psychedelic hallucinogens in anesthetized rats, although decreasing spontaneous activity, produces a paradoxical facilitation of the activation of LC neurons by sensory stimuli (Aghajanian 1980; Rasmussen and Aghajanian 1986); this effect is not through a direct action on LC cell bodies, because it cannot be mimicked by the local, microiontophoretic application of the drugs. The effects of hallucinogens on LC neurons can be reversed by low intravenous doses of selective 5-HT 2 antagonists, such as ritanserin (Rasmussen and Aghajanian 1986). Antipsychotic drugs are also able to reverse the actions of hallucinogens in the locus coeruleus at doses correlating with their affinity for 5-HT 2A but not dopamine and adrenergic receptors Because the effects of systemically administered hallucinogens are through an activation of afferent inputs rather than through a direct action upon LC cell bodies, the LC itself cannot be used as a model for studying the direct cellular actions of hallucinogens. Nevertheless, the effects of the hallucinogens upon the LC are of interest, because this nucleus receives such an extraordinarily widespread convergence of sensory information, both somatosensory and visceral, relaying this information to virtually all other parts of the neuraxis, including the cerebral cortex. 5-HT 2A Receptors Enhance Glutamate Release in Neocortex The ubiquitous effects of hallucinogens on such complex processes as cognition, perception, and mood suggest the involvement of the cerebral cortex. The direct, postsynaptic effect of 5-HT in the cortex are variable: depolarization, hyperpolarization, or no change, depending upon whether the effects of excitatory 5-HT 2 receptors or inhibitory 5-HT 1A receptors are predominant in any given layer V pyramidal cell Whole-cell patch clamp recordings have demonstrated that 5-HT induces a small, but significant, increase in the amplitude of spontaneous EPSCs, an effect that may involve a postsynaptic amplification mechanism (Aghajanian and Marek 1997). Such a postsynaptic effect is consistent with the finding of a high density of 5-HT 2A receptor immunoreactivity in the apical dendrites of cortical pyramidal cells (Jakab and GoldmanRakic 1998; A Focal Mechanism for 5-HT 2A -Induced Glutamate Release onto Apical Dendrites of Layer V Pyramidal Cells A novel mechanism, independent of impulse flow, seems to be involved in the increase in glutamate release induced by 5-HT 2A receptor activation. Blockade of 5-HT-induced EPSCs by bath application of the fast sodium channel blocker tetrodotoxin (TTX) or perfusion of the slice with a solution containing no added calcium ("0" calcium) would generally suggest that 5-HT had activated glutamatergic cells in the slice, leading to an impulse-flow-dependent release of glutamate. Several lines of evidence argue against this conventional interpretation. First, we rarely found any neurons induced to fire by bath application of 5-HT (unlike our experience in the piriform cortex, where we readily found GABAergic interneurons excited by 5-HT). Second, none of the pyramidal cells (a potential source of intracortical excitatory inputs) in our sample were depolarized by 5-HT sufficiently to reach threshold for firing. Third, EPSCs could be induced by the microiontophoresis of 5-HT onto the apical dendrites of layer V pyramidal cells, but no cell firing was detected while recording extracellularly through the microiontophoretic electrod

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Modeling “psychosis” in vitro by inducing disordered neuronal network activity in cortical brain slices

# The Author(s) 2009. This article is published with open access at Springerlink.com Introduction Dysregulation of neuronal networks has been suggested to underlie the cognitive and perceptual abnor-malities observed schizophrenia. Discussions An in vitro model of psychosis is proposed based on the two different approaches to cause aberrant networ

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

The Role of UPF0157 in the Folding of M. tuberculosis Dephosphocoenzyme A Kinase and the Regulation of the Latter by CTP

BACKGROUND:Targeting the biosynthetic pathway of Coenzyme A (CoA) for drug development will compromise multiple cellular functions of the tubercular pathogen simultaneously. Structural divergence in the organization of the penultimate and final enzymes of CoA biosynthesis in the host and pathogen and the differences in their regulation mark out the final enzyme, dephosphocoenzyme A kinase (CoaE) as a potential drug target. METHODOLOGY/PRINCIPAL FINDINGS:We report here a complete biochemical and biophysical characterization of the M. tuberculosis CoaE, an enzyme essential for the pathogen's survival, elucidating for the first time the interactions of a dephosphocoenzyme A kinase with its substrates, dephosphocoenzyme A and ATP; its product, CoA and an intrinsic yet novel inhibitor, CTP, which helps modulate the enzyme's kinetic capabilities providing interesting insights into the regulation of CoaE activity. We show that the mycobacterial enzyme is almost 21 times more catalytically proficient than its counterparts in other prokaryotes. ITC measurements illustrate that the enzyme follows an ordered mechanism of substrate addition with DCoA as the leading substrate and ATP following in tow. Kinetic and ITC experiments demonstrate that though CTP binds strongly to the enzyme, it is unable to participate in DCoA phosphorylation. We report that CTP actually inhibits the enzyme by decreasing its Vmax. Not surprisingly, a structural homology search for the modeled mycobacterial CoaE picks up cytidylmonophosphate kinases, deoxycytidine kinases, and cytidylate kinases as close homologs. Docking of DCoA and CTP to CoaE shows that both ligands bind at the same site, their interactions being stabilized by 26 and 28 hydrogen bonds respectively. We have also assigned a role for the universal Unknown Protein Family 0157 (UPF0157) domain in the mycobacterial CoaE in the proper folding of the full length enzyme. CONCLUSIONS/SIGNIFICANCE:In view of the evidence presented, it is imperative to assign a greater role to the last enzyme of Coenzyme A biosynthesis in metabolite flow regulation through this critical biosynthetic pathway

Epistasis among Presynaptic Serotonergic System Components

Epistatic interactions among regulatory components of the serotonin (5-HT) neurotransmitter system may be an important aspect of 5-HT function. Because 5-HT dysregulation is associated with several common psychiatric disorders, the potential for epistasis among genetic variants in the 5-HT transporter (SERT), 5-HT 1B terminal autoreceptor and the 5-HT 1A somatodendritic autoreceptor should be examined. In this study, output from a dynamic minimal model of 5-HT function was compared to empirical results in the literature. Parameters representing extracellular 5-HT clearance rates (SERT), 5-HT release levels (5-HT 1B ) and inhibitory thresholds (the amount of extracellular 5-HT above which cell firing is inhibited, an indication of 5-HT 1A autoreceptor sensitivity) were varied to simulate genetic deletion (i.e. knockout) of each component singly, and in combination. Simulated knockout effects on extracellular 5-HT level and presynaptic neural firing rates were in the same direction and of similar relative magnitude as studies in the literature. Epistasis among presynaptic components appears to be important in the 5-HT system’s regulation of extracellular 5-HT levels, but not of firing rates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44113/1/10519_2004_Article_1019.pd

Targeted anti-vascular therapies for ovarian cancer: current evidence

Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis

Exploiting the therapeutic potential of the PI3K-AKT-mTOR pathway in enriched populations of gynecologic malignancies

Given the prevalence of phosphatase & tensin homolog mutations in histologic specimens harvested from patients with endometrial cancer, significant interest in systemic treatment with PI3K/Akt/mTOR inhibitors has emerged. Several Phase II trials have been completed studying mTOR inhibitors in advanced/recurrent endometrial cancer. The mTOR pathway also appears to be important in some cervical cancers. Finally, because clear cell carcinoma of the ovary and renal cell carcinoma have a shared histology, the potential for activity of mTOR inhibitors in clear cell cancer of the ovary is implicit. This article reviews the results of Phase II clinical trials of PI3K/Akt/mTOR pathway inhibitors in patients with endometrial cancer, and discusses the potential therapeutic landscape of mTOR inhibition in enriched populations in gynecologic cancers