DOCSLIB.ORG

Pipeline of Medications to Treat Substance Use Disorders

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Pipeline of Medications to Treat

Substance Use Disorders

Iván D. Montoya, M.D., M.P.H.

Clinical Director and Deputy Director
Division of Therapeutics and Medical Consequences
NIDA

• Cocaine • Methamphetamine • Cannabis

Outline

Past-Year Prevalence

NSDUH, 2018

Past-Year Prevalence

NSDUH, 2018

Number of Overdose Deaths

CDC, 2018

Molecular Neurobiology of Stimulant Use Disorders

Glutamate

Excitatory Input

Enkephalin or Dynorphin
Inhibitory Neuron

k Opioid Receptors
Dopamine Receptors

Enkephalin Inhibitory Neuron

Dopamine Neuron

GABA Neuron

m Opioid Receptors

REWARD

GABA-A Receptors

GABA Inhibitory Feedback

Presynaptic
Opioid Receptors
(m, d?)

GABA
Inhibitory Neuron

Ventral Tegmental Area

(VTA)
Nucleus Accumbens
(NAc)
Adapted from Koop, 2016

•••••••

5HT2c Agonist - Lorcaserin (Belviq XR®) Orexin 1 antagonists

Cocaine

EMB-101 (Oxazepam + Metyrapone) Buprenorphine + Opioid Antagonist Ketamine

– Clinical Studies

Oxytocin L-Tetrahydropalmatine (L-THP)

5-HT2C Agonist - Lorcaserin

• Clinically available

• Selective agonist

• Modulate mesolimbic dopamine, decreasing dopamine release

• FDA-approved for weight loss

• Lorcaserin (Belviq®)10 mg bid • Lorcaserin XR (Belviq XR®) 20 mg qd

• Schedule IV

• Arena Pharmaceuticals - Eisai Inc.

Lorcaserin Pre-clinical Studies - Stimulants

• Decrease cocaine self-administration and the reinstatement of responding for cocaine (Grottick et al., 2000;

Burmeister et al., 2004; Burbassi and Cervo 2008; Cunningham et al., 2011; Manvich et al., 2012; RüediBettschen et al., 2015, Howell and Cunningham 2015).

• Attenuates self-administration of cocaine (Collins et al., 2016; Harvey-Lewis et al., 2016) and nicotine (Levin et al.,
2011; Higgins et al., 2012, 2013)

• Tolerance does not develop to the effects of lorcaserin on cocaine self-administration (Collins et al., 2016) • Attenuates the ability of stress or conditioned cues to stimulate cocaine-seeking behavior in rats with a prior history of cocaine self-administration (Fletcher et al., 2008)

• Efficacy against methamphetamine cue reinstatement and nicotine

Selective serotonin 2C receptor agonist Modulates the dopaminergic reward system. Approved by the FDA for chronic weight management

Lorcaserin – Clinical Trials

NCT03007394

• Phase 2 multicenter RCT - NIDA • N=272 • 10 mg bid * 13 weeks • Recruitment complete • Data analysis in progress • Primary endpoint:proportion of subjects that successfully achieve abstinence from cocaine during the last three weeks of treatment in the "pre-qualified for primary efficacy endpoint" (PPEE) population [ Time Frame: Treatment weeks 11 - 13 ]

NCT03192995

• Pilot RCT (n=45) UCSF

Orexin (Hypocretin) Neurons

- 10,000–20,000 orexin-producing neurons in the human brain - Located predominantly in the perifornical area and lateral hypothalamus - Project widely throughout the central nervous system - There are two types of orexin peptide and two types of orexin receptor - Regulates arousal, wakefulness, reproduction, and appetite.

Peyron et al. J. Neurosci. 1998;18:9996-10015

OX1 Antagonists and Cocaine

• Reduce dopamine transporter sensitivity to cocaine in the VTA and NAc • Disrupt the expression of Pavlovian associations formed by cocaine • Reduce compulsive-like cocaine taking under long access self-

administration conditions

• Suppress motivation to obtain cocaine under high effort conditions • Reduce the strength of stress-,cue- and context-induced cocaine

reinstatement.

Orexin 1 Antagonists – Why clinically?

• Sleep problems frequently precede SUD • Sleep is directly impaired by SUD
• Drug (opioids) modify the sleep-wake cycle (Orexin system)

• Drug withdrawal associated with sleep disruptions • Sleep problems have been independently associated with increased comorbidity • Benzodiazepines are frequently abused in conjunction with opioids
• Benzodiazepines co-administration with opioid agonists is associated with increased lethality

Suvorexant

• Dual OX1R/OX2R antagonist and schedule IV compound, FDA

approved for treatment of insomnia

• Suvorexant (10 mg vs placebo) in reducing anxiety, improving sleep, and reducing cocaine cravings or cocaine use(n=20)

• Urine samples positive for cocaine: 90% vs 82%

• Preliminary evidence favoring Suvorexant for inhibitory control, sleep,

stress reactivity, and craving. (Lane, 2018)

• NCT03937986: Human lab Study. PI: Bill Stoops.

• Mirtazapine • Monoclonal Antibody • Vaccine

Methamphetamine

• Naltrexone

• Ibudilast

– Clinical Studies

• Bupropion • Buspirone • Oxytocin

Mirtazapine

• Potent antagonist or inverse agonist of the α2A-, α2B-

, and α2C-adrenergic receptors, the serotonin 5-

HT2A, 5-HT2C, and the histamine H1 receptor
• Does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase.

• Safe and no abuse potential • SE: somnolence, weight gain, dry mouth • May reduce meth craving (Kingsakon, 2005)

Mirtazapine

N=56 Mirtazapine 30 mg qd

D-B RCT

Weekly urine

Colfax, 2011

• Phase 1, double-blind, randomized, placebo-controlled, ascending single-dose safety

and tolerability study
• ch-mAb7F9 administered as an intravenous infusion to healthy volunteers • Forty-two subjects were treated in 5 dose groups ranging from 0.2 to 20 mg/kg

ch-mAb7F9, with 10 of the 42 subjects receiving normal saline as a placebo control.

• Subjects were followed for 147 d after dosing with regular safety assessments and for pharmacokinetic and immunogenicity analyses.

• It is predicted that 20 mg/kg will be effective in humans

• The concentration of ch-mAb7F9 required to bind this much METH is »50 mg/mL

• Ch-mAb7F9 concentrations remain above 50 mg/ml for 1 to 2 weeks after 6 mg/kg, and for about 5 weeks after 20 mg/kg

Past-Year Prevalence

NSDUH, 2018

• Fatty acid amide hydrolase (FAAH): enzyme that degrades the

endocannabinoid anandamide
• FAAH inhibition  Increase anandamide • double-blind, placebo-controlled, parallel group phase 2a trial at one site in

men aged 18–55 years with cannabis dependence

• Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as

outpatients

FAAH Inhibitor F-04457845

Neuropsychopharmacology, Dec 2018

Summary

• Cocaine

• Lorcaserin

• Methamphetamine

• Mirtazepine • Monoclonal antibody

• Cannabis

• FAAH Inhibitor

Preclinical Pharmacological Targets

• Vesicle Monoaminte Transporter 2 (VMAT2)

• Neurotensing Receptor 1 (NTR1)

• Trace Amine-Associated Receptor 1 (TAAR1) • Organic Cation Transporter 3 • Chemokine receptor type 4 (CXCR-4) • Ghrelin Receptor Antagonist

• Muscarinic M5

• Nociceptive Orphanin Receptor (NOP/ORL) • Metabotropic Glutamate 2/3 Receptor (mGLUR2/3)

Past-Year Prevalence – Thousands of People

Bolliger, 2019

Recommended publications
  • Dual Orexin Receptor Antagonist Induces Changes in Core Body

    Dual Orexin Receptor Antagonist Induces Changes in Core Body

    www.nature.com/scientificreports Corrected: Author Correction OPEN Dual orexin receptor antagonist induces changes in core body temperature in rats after exercise Tristan Martin1, Yves Dauvilliers2, Ouma-Chandrou Koumar1, Valentine Bouet1, Thomas Freret1, Stéphane Besnard1, François Dauphin1 & Nicolas Bessot1* Hypothalamic orexin neurons are involved in various physiological functions, including thermoregulation. The orexinergic system has been considered as a potent mediator of the exercise response. The present study describes how the antagonization of the orexinergic system by a dual orexin receptor antagonist (DORA) modifes the thermoregulatory process during exercise. Core Body Temperature (CBT) and Spontaneous Locomotor Activity (SLA) of 12 male Wistar rats were recorded after either oral administration of DORA (30 mg/kg or 60 mg/kg) or placebo solution, both at rest and in exercise conditions with treadmill running. DORA ingestion decreased SLA for 8 hours (p < 0.001) and CBT for 4 hours (p < 0.01). CBT (°C) response was independent of SLA. The CBT level decreased from the beginning to the end of exercise when orexin receptors were antagonized, with a dose-dependent response (39.09 ± 0.36 and 38.88 ± 0.28 for 30 and 60 mg/kg; p < 0.001) compared to placebo (39.29 ± 0.31; p < 0.001). CBT increased during exercise was also blunted after DORA administration, but without dose efects of DORA. In conclusion, our results favor the role of orexin in the thermoregulation under stress related to exercise conditions. Core Body Temperature (CBT) is modulated by heat production and dissipation mechanisms controlled by the hypothalamus. Tis generates patterns of autonomic, endocrine, motor, and behavioral responses to adapt to environmental challenges1.
  • Diverse Functional Autoantibodies in Patients with COVID-19

    Diverse Functional Autoantibodies in Patients with COVID-19

    medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20247205; this version posted December 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Diverse Functional Autoantibodies in Patients with COVID-19 Eric Y. Wang1,*, Tianyang Mao1,*, Jon Klein1,*, Yile Dai1,*, John D. Huck1, Feimei Liu1, Neil S. Zheng1, Ting Zhou1, Benjamin Israelow1, Patrick Wong1, Carolina Lucas1, Julio Silva1, Ji Eun Oh1, Eric Song1, Emily S. Perotti1, Suzanne Fischer1, Melissa Campbell5, John B. Fournier5, Anne L. Wyllie3, Chantal B. F. Vogels3, Isabel M. Ott3, Chaney C. Kalinich3, Mary E. Petrone3, Anne E. Watkins3, Yale IMPACT Team¶, Charles Dela Cruz4, Shelli F. Farhadian5, Wade L. Schulz6,7, Nathan D. Grubaugh3, Albert I. Ko3,5, Akiko Iwasaki1,3,8,#, Aaron M. Ring1,2,# 1 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA 2 Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA 3 Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA 4 Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale School of Medicine, New Haven, CT, USA 5 Department of Internal Medicine (Infectious Diseases), Yale School of Medicine, New Haven, CT, USA 6 Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA 7 Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA 8 Howard Hughes Medical Institute, Chevy Chase, MD, USA * These authors contributed equally to this work ¶ A list of authors and their affiliations appears at the end of the paper # Correspondence: [email protected] (A.M.R.); [email protected] (A.I.) 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
  • Molecular Insights Into the Transmembrane Domain of the Thyrotropin Receptor

    Molecular Insights Into the Transmembrane Domain of the Thyrotropin Receptor

    Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor Vanessa Chantreau, Bruck Taddese, Mathilde Munier, Louis Gourdin, Daniel Henrion, Patrice Rodien, Marie Chabbert To cite this version: Vanessa Chantreau, Bruck Taddese, Mathilde Munier, Louis Gourdin, Daniel Henrion, et al.. Molecu- lar Insights into the Transmembrane Domain of the Thyrotropin Receptor. PLoS ONE, Public Library of Science, 2015, 10 (11), pp.e0142250. 10.1371/journal.pone.0142250. hal-02318838 HAL Id: hal-02318838 https://hal.archives-ouvertes.fr/hal-02318838 Submitted on 17 Oct 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. RESEARCH ARTICLE Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor Vanessa Chantreau1, Bruck Taddese1, Mathilde Munier1, Louis Gourdin1,2, Daniel Henrion1, Patrice Rodien1,2, Marie Chabbert1* 1 UMR CNRS 6214 –INSERM 1083, Laboratory of Integrated Neurovascular and Mitochondrial Biology, University of Angers, Angers, France, 2 Reference Centre for the pathologies of hormonal receptivity, Department of Endocrinology, Centre Hospitalier Universitaire of Angers, Angers, France * [email protected] Abstract The thyrotropin receptor (TSHR) is a G protein-coupled receptor (GPCR) that is member of the leucine-rich repeat subfamily (LGR).
  • Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

    Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

    Neuropeptides Controlling Energy Balance: Orexins and Neuromedins Joshua P. Nixon, Catherine M. Kotz, Colleen M. Novak, Charles J. Billington, and Jennifer A. Teske Contents 1 Brain Orexins and Energy Balance ....................................................... 79 1.1 Orexin............................................................................... 79 2 Orexin and Feeding ....................................................................... 80 3 Orexin and Arousal ....................................................................... 83 J.P. Nixon • J.A. Teske Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA C.M. Kotz (*) Veterans Affairs Medical Center, GRECC (11 G), Minneapolis, MN, USA Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA e-mail: [email protected] C.M. Novak Department of Biological Sciences, Kent State University, Kent, OH, USA C.J. Billington Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Veterans Affairs Medical Center, Endocrine Unit (111 G), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA H.-G. Joost (ed.), Appetite Control, Handbook of Experimental Pharmacology 209, 77 DOI 10.1007/978-3-642-24716-3_4, # Springer-Verlag Berlin Heidelberg 2012 78 J.P. Nixon et al. 4 Orexin Actions on Endocrine and Autonomic Systems ................................. 84 5 Orexin, Physical Activity, and Energy Expenditure ....................................
  • Identification of Neuropeptide Receptors Expressed By

    Identification of Neuropeptide Receptors Expressed By

    RESEARCH ARTICLE Identification of Neuropeptide Receptors Expressed by Melanin-Concentrating Hormone Neurons Gregory S. Parks,1,2 Lien Wang,1 Zhiwei Wang,1 and Olivier Civelli1,2,3* 1Department of Pharmacology, University of California Irvine, Irvine, California 92697 2Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697 3Department of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697 ABSTRACT the MCH system or demonstrated high expression lev- Melanin-concentrating hormone (MCH) is a 19-amino- els in the LH and ZI, were tested to determine whether acid cyclic neuropeptide that acts in rodents via the they are expressed by MCH neurons. Overall, 11 neuro- MCH receptor 1 (MCHR1) to regulate a wide variety of peptide receptors were found to exhibit significant physiological functions. MCH is produced by a distinct colocalization with MCH neurons: nociceptin/orphanin population of neurons located in the lateral hypothala- FQ opioid receptor (NOP), MCHR1, both orexin recep- mus (LH) and zona incerta (ZI), but MCHR1 mRNA is tors (ORX), somatostatin receptors 1 and 2 (SSTR1, widely expressed throughout the brain. The physiologi- SSTR2), kisspeptin recepotor (KissR1), neurotensin cal responses and behaviors regulated by the MCH sys- receptor 1 (NTSR1), neuropeptide S receptor (NPSR), tem have been investigated, but less is known about cholecystokinin receptor A (CCKAR), and the j-opioid how MCH neurons are regulated. The effects of most receptor (KOR). Among these receptors, six have never classical neurotransmitters on MCH neurons have been before been linked to the MCH system. Surprisingly, studied, but those of most neuropeptides are poorly several receptors thought to regulate MCH neurons dis- understood.
  • Supplementary Table 2

    Supplementary Table 2

    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942
  • Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4, Reduces Reinstatement of Heroin Seeking Behavior in Rats

    Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4, Reduces Reinstatement of Heroin Seeking Behavior in Rats

    bioRxiv preprint doi: https://doi.org/10.1101/730408; this version posted August 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Glucagon-like peptide-1 receptor agonist, exendin-4, reduces reinstatement of heroin seeking behavior in rats Joaquin E. Douton1, Corinne Augusto1, Brooke A Stultzfus1, Nurgul Salli2, Kent E. Vrana2, and Patricia S. Grigson1 1 Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania, United States of America 2 Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America. Corresponding Author: Patricia Sue Grigson, Ph.D. Department of Neural and behavioral Sciences Penn State College of Medicine Hershey, PA 17033 Phone: 717-531-5772 Fax: 717-531-6919 Email: [email protected] Short/running title: Effects of Ex-4 on heroin seeking Keywords: Opioid, Addiction, Treatment, Individual Differences, Self-administration, Relapse bioRxiv preprint doi: https://doi.org/10.1101/730408; this version posted August 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 2 Abstract Background Studies have shown that ‘satiety’ agents such as exendin-4 (a glucagon-like peptide-1 analog) reduce responding for addictive drugs (e.g., cocaine, nicotine, alcohol).
  • Mapping the Hypocretin/Orexin Neuronal System: an Unexpectedly Productive Journey

    Mapping the Hypocretin/Orexin Neuronal System: an Unexpectedly Productive Journey

    2268 • The Journal of Neuroscience, March 1, 2017 • 37(9):2268–2272 Progressions Author reflections on developments since the publication of “Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems,” by Christelle Peyron, Devin K. Tighe, Anthony N. van den Pol, Luis de Lecea, H. Craig Heller, J. Gregor Sutcliffe and Thomas S. Kilduff. (1998) J Neurosci 18:9996–10015. Mapping the Hypocretin/Orexin Neuronal System: An Unexpectedly Productive Journey Christelle Peyron1 and Thomas S. Kilduff2 1Center for Research in Neuroscience of Lyon, Sleep team, Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche 5292, Institut National de la Sante´ et de la Recherche Me´dicale U1028, Universite´ Claude Bernard Lyon 1, Lyon, France, and 2Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California 94025 Early in 1998, we (de Lecea et al., 1998) and others (Sakurai et al., 1998) described the same hypothalamic neuropeptides, respectively called the hypocretins or orexins, which were discovered using two different approaches. In December of that year, we published the subject of this commentary in the Journal of Neuroscience: a highly detailed anatomical description of the extensive axonal projections of the hypocretin/orexin neurons. Although the function of this system was unknown at the time, a large body of literature today attests that the hypocretin/orexin neuropeptides play important roles in multiple physiological functions, particularly in sleep/wake regulation. Neuroanatomical studies are rarely frontline news, but the citation rate of this paper underscores the critical nature of such basic research. Based in part on this detailed description, the hypocretin/orexin neuropeptides have since been studied in many different areas of neuroscience research, including sleep/wake regulation, feeding, addiction, reward and motivation, anxiety and depression, cardio- vascular regulation, pain, migraine, and neuroendocrine regulation, including reproduction.
  • Sfn2015 Items of Interest

    Sfn2015 Items of Interest

    Presentations and Posters of Interest Society for Neuroscience Meeting (2015) 34.01/A100. Estradiol rapidly attenuates ORL-1 receptor-mediated inhibition of proopiomelanocortin neurons via Gq-coupled, membrane-initiated signaling *K. M. CONDE1, C. MEZA2, M. KELLY3, K. SINCHAK4, E. WAGNER2; 1Grad. Col. of Biomed. Sci., 2Col. of Osteo. Med. of the Pacific, Western Univ. of Hlth. Sci., Pomona, CA; 3 Dept. of Physiol. & Pharmacol., Oregon Hlth. and Sci. Univ., Portland, OR; 4California State University, Long Beach, Long Beach, CA Ovarian estrogens act through multiple receptor signaling mechanisms that converge on hypothalamic arcuate nucleus (ARH) proopiomelanocortin (POMC) neurons. A subpopulation of these neurons project to the medial preoptic nucleus (MPN) to regulate lordosis. Orphanin FQ/nociception (OFQ/N) via its opioid-like receptor (ORL-1) regulates lordosis through direct actions on these MPN-projecting POMC neurons. Based o an ever-burgeoning precedence for fast steroid actions, we explored whether estradiol excites ARH POMC neurons by rapidly attenuating inhibitory ORL-1 signaling in these cells. Experiments were carried out in hypothalamic slices prepared from ovariectomized female rats injected one-week prior with the retrograde tracer Fluorogold into the MPN. During electrophysiologic recordings, cells were held at or near -60 mV. Post-hoc identification of neuronal phenotype was determined via immunohistofluorescence. In vehicle-treated slices OFQ/N caused a robust outward current/hyperpolarization via activation of GIRK channels. This OFQ/N-induced outward current was attenuated by 17-β estradiol (E2, 100nM). The 17α enantiomer of E2 had n effect. The OFQ/N-induced response was also attenuated by an equimolar concentration of E2 conjugated to BSA.
  • Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

    Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

    fphar-08-00357 June 7, 2017 Time: 17:43 # 1 ORIGINAL RESEARCH published: 09 June 2017 doi: 10.3389/fphar.2017.00357 Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation Pascal Bonaventure1*, Christine Dugovic1, Brock Shireman1, Cathy Preville1, Sujin Yun1, Brian Lord1, Diane Nepomuceno1, Michelle Wennerholm1, Timothy Lovenberg1, Nicolas Carruthers1, Stephanie D. Fitz2, Anantha Shekhar2,3 and Philip L. Johnson4,3 1 Janssen Research & Development, LLC, San Diego, CA, United States, 2 Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States, 3 Stark Neurosciences Research Institute, Indiana University School of 4 Edited by: Medicine, Indianapolis, IN, United States, Department of Anatomy and Cell Biology, Indiana University School of Medicine, Yukihiro Ohno, Indianapolis, IN, United States Osaka University of Pharmaceutical Sciences, Japan Orexin neurons originating in the perifornical and lateral hypothalamic area are Reviewed by: highly reactive to anxiogenic stimuli and have strong projections to anxiety and Kenji Hashimoto, Chiba University, Japan panic-associated circuitry. Recent studies support a role for the orexin system Karolina Pytka, and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress Jagiellonian University, Poland response. However, no selective OX1R antagonist has been systematically tested *Correspondence: Pascal Bonaventure in two preclinical models of using panicogenic stimuli that induce panic attack [email protected] in the majority of people with panic disorder, namely an acute hypercapnia-panic provocation model and a model involving chronic inhibition of GABA synthesis in Specialty section: This article was submitted to the perifornical hypothalamic area followed by intravenous sodium lactate infusion.
  • Narcolepsy and Influenza Vaccination—The Inappropriate Awakening of Immunity

    Narcolepsy and Influenza Vaccination—The Inappropriate Awakening of Immunity

    Editorial Page 1 of 6 Narcolepsy and influenza vaccination—the inappropriate awakening of immunity Anoma Nellore1, Troy D. Randall2,3 1Department of Medicine, Division of Infectious Diseases; 2Division of Clinical Immunology, 3Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA Correspondence to: Troy D. Randall. Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Birmingham, 1720 2nd AVE S. SHEL 507, Birmingham, AL 35294, USA. Email: [email protected]. Submitted Sep 24, 2016. Accepted for publication Sep 27, 2016. doi: 10.21037/atm.2016.10.60 View this article at: http://dx.doi.org/10.21037/atm.2016.10.60 Introduction are associated with the onset of narcolepsy symptoms. However, the way these infections promote the onset of Narcolepsy is a chronic neurological disorder characterized narcolepsy is not entirely clear. by an inability to regulate sleep/wake cycles leading to abruptly occurring periods of daytime sleepiness, cataplexy, hypnogogic hallucinations and disrupted nocturnal sleep (1). Link with influenza vaccination The symptoms of narcolepsy often emerge over time and The appearance of the H1N1 pandemic strain of influenza a definitive diagnosis requires a combination of behavioral in 2009 prompted the rapid development and distribution and biochemical tests. As a result, the identification of of vaccines containing antigens from the new virus. These narcolepsy in any particular patient is difficult and is often delayed by up to a decade following the initial onset of vaccines included (among others), Pandemrix, which was symptoms. administered to approximately 30M patients in Europe, The symptoms of narcolepsy are due to impaired Focetria, which was administered to approximately 25M signaling by the neuropeptide, hypocretin (HCRT— patients globally, including Europe, and Arepanrix, which also known as orexin) (2-4).
  • Regulatory Role of Orexin in the Antistress Effect of “Press Tack Needle” Acupuncture Treatment

    Regulatory Role of Orexin in the Antistress Effect of “Press Tack Needle” Acupuncture Treatment

    healthcare Article Regulatory Role of Orexin in the Antistress Effect of “Press Tack Needle” Acupuncture Treatment Aki Fujiwara 1,2, Mana Tsukada 1, Hideshi Ikemoto 1 , Takuji Izuno 1, Satoshi Hattori 1, Takayuki Okumo 1 , Tadashi Hisamitsu 1 and Masataka Sunagawa 1,* 1 Department of Physiology, School of Medicine, Showa University, Tokyo 142-8555, Japan; [email protected] (A.F.); [email protected] (M.T.); [email protected] (H.I.); [email protected] (T.I.); [email protected] (S.H.); [email protected] (T.O.); [email protected] (T.H.) 2 Acupuncture & Moxibustion Clinic Tenshinotamago, Tokyo 104-0061, Japan * Correspondence: [email protected]; Tel.: +81-3-3784-8110 Abstract: The aim of this research was to investigate the antistress effect of press tack needle (PTN) acupuncture treatment using rats with social isolation stress (SIS). Rats were divided into non-stress group (Grouped+sham), stress group (SIS+sham), and PTN-treated SIS group (SIS+PTN). Rats in the SIS+PTN and SIS+sham groups were housed alone for eight days. For the SIS+PTN group, a PTN (length, 0.3 or 1.2 mm) was fixed on the GV20 acupoint on day 7. We measured stress behavior based on the time the rats showed aggressive behavior and the levels of plasma corticosterone and orexin A on day 8. In addition, the orexin-1 receptor or orexin-2 receptor antagonist was administered to rats that were exposed to SIS. The duration of aggressive behavior was significantly prolonged in the SIS+sham group, and the prolonged duration was inhibited in the SIS+PTN (1.2 mm) group.