DOCSLIB.ORG

Atypical Neuroleptics Have Low Affinity for Dopamine D2 Receptors Or Are Selective for D 4 Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Atypical Neuroleptics Have Low Affinity for Dopamine D2 Receptors Or Are Selective for D 4 Receptors ELSEVIER REVIEW Atypical Neuroleptics Have Low Affinity for Dopamine D2 Receptors or Are Selective for D 4 Receptors Philip Seeman, M.D., Ph.D., Roy Corbett, Ph.D., and Hubert H. M. Van Toi, Ph.D. This review examines the possible receptor basis of the For example, clozapine revealed a radioligand-independent atypical action of those atypical antipsychotic drugs that value of 1.6 nM at the dopamine D4 receptor, agreeing with elicit low levels of Parkinsonism. Such an examination the value directly measured with [3H]-clozapine at D4. requires consistent and accurate dissociation constants for However, because clozapine competes with endogenous the antipsyclwtic drugs at the relevant dopamine and dopamine, the in vivo concentration of clozapine (to occupy serotonin receptors. It has long been known, however, that dopamine D4 receptors) can be derived to be about 13 nM, the dissociation constant of a given antipsychotic drug at agreeing with the value of 12 to 20 nM in the plasma water the dopamine D2 receptor varies between laboratories. or spinal fluid observed in treated patients. The atypical Although such variation depends on several factors, it has neuroleptics remoxipride, clozapine, perlapine, seroquel, recently been recognized that the radioligand used to and melperone had low affinity for the dopamine D2 measure the competition between the antipsychotic drug receptor (radioligand-independent dissociation constants of and the radioligand is an important variable. The present 30 to 90 nM). Such low affinity makes these latter five review summarizes information on this radioligand drugs readily displaceable by high levels of endogenous dependence. In general, a radioligand of low solubility in dopamine in the caudate or putamen. Most typical the membrane (i.e., low tissue:buffer partition) results in a neuroleptics have radioligand-independent values of 0.3 to low value for the antipsychotic dissociation constant when 5 nM at dopamine D2 receptors, making them more the drug competes with the radioligand. Hence, by first resistant to displacement by endogenous dopamine. Finally, obtaining the antipsychotic dissociation constants using a relation was found between the neuroleptic doses for rat different radioligands of different solubility in the catalepsy and the D2:D4 ratio of the radioligand­ membrane, one can then extrapolate the data to low or independent K values for these two receptors. Thus, the "zero" ligand solubility. The extrapolated value represents atypical neuroleptics appear to fall into two groups, those the radioligand-independent dissociation constant of the that have a low affinity for dopamine D2 receptors and those antipsychotic. These values are here given for dopamine D2 that are selective for dopamine D4 receptors. © 1997 and D4 receptors, as well as for serotonin 5-HT2A receptors. American College of Neuropsychopharmacology These values, rnoreover, agree with the dissociation constant [Neuropsychopharmacology 16:93-110, 1997] directly obtained with the radioactive antipsychotic itself. ------ KEY WORDS: Dopamine D4 receptors; Neuroleptics; Serotonin 2 receptors; Parkinsonism; Clozapine; Catalepsy ------------ From the Departments of Pharmacology (PS, HHMVT) and of Address correspondence to: Philip Seeman, M.D., Ph.D., Depart­ Psychiatry, and the Molecular Neurobiology Laboratory (HHMVT) ment of Pharmacology, Medical Science Building, Room 4344, Uni­ University of Toronto, Toronto, Canada; and the Department of Bio­ versity of Toronto, Toronto, Ontario, Canada M5S 1A8. logical Research (RC), Hoechst-Roussel Pharmaceuticals Inc., Som­ Re~eived January 30, 1996; revised May 19, 1996; accepted May erville, NJ. 27, 1996. NEUROPSYCHOPHARMACOLOGY 1997-VOL. 16, NO. 2 © 1997 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/97 /$17.00 655 Avenue of the Americas, New York, NY 10010 PI! S0893-133X(96)00187-9 94 P. Seeman et al. NEUROPSYCHOPHARMACOLOGY 1997-VOL. 16, NO. 2 RECEPTOR HYPOTHESES FOR ATYPICAL membrane also determines the membrane:buffer parti­ NEUROLEPTIC ACTION tion coefficient of neuroleptics (Kwant and Seeman 1969), as does the membrane lipid composition (Kwant and The blockade of dopamine D2 receptors alleviates psy­ Seeman 1971). Many of these physicochemical factors, chosis but also produces Parkinsonism (Seeman et al. including temperature, that affect the partition of the 1974, 1975; Creese et al. 1976; Seeman 1992a, 1995a). An­ neuroleptic in the membrane have been previously re­ tipsychotic drugs (neuroleptics) that elicit few or none viewed (Seeman 1972). As for the role of physicochemi­ of the extrapyramidal signs of Parkinsonism are re­ cal factors on the dissociation constant of agonists and ferred to as atypical antipsychotic drugs (Meltzer and antagonists, the sodium and magnesium ion concentra­ Nash 1991). What is the receptor basis for this atypical tions determine the proportion of the dopamine D2 re­ action of these particular neuroleptics? There are sev­ ceptors that are in the high-affinity state (Grigoriadis eral current views: and Seeman 1985; Watanabe et al. 1985). Sodium also is essential for the high-affinity binding of benzamide 1. Some atypical neuroleptics may have a low affinity neuroleptics to dopamine receptors (Jarvie et al. 1987). for dopamine D2 receptors and may thus be readily Nevertheless, despite standard laboratory experi­ displaced by high endogenous concentrations of mental conditions internationally (e.g., pH of 7.4 and dopamine in the caudate or putamen. physiological concentrations of Na+, Mg++, and other 2. Atypical neuroleptics may block both dopamine D 2 ions), it has long been known that the dissociation con­ receptors and muscarinic receptors. stant of a particular neuroleptic may vary considerably 3. Atypical neuroleptics may have a balanced block of between laboratories, particularly when different radio­ dopamine D2 receptors and serotonin2A (5-HT2A) re­ ligands are used. For example, the dissociation constant ceptors (Meltzer 1989, 1995; Leysen et al. 1994; Hut­ for clozapine at the dopamine D receptor is approxi­ tunen 1995). 2 mately 150 nM (range 70-400 nM), when using [3H]­ 4. Atypical neuroleptics may selectively block dopa­ spiperone as a radioligand (Seeman 1992a). However, mine D receptors. 4 when [3H]-raclopride is used as the radioligand, the dis­ We examined these various hypotheses after first sociation constant for clozapine at D2 is between 35 and considering the values for the neuroleptic dissociation 60 nM (Malmberg et al. 1993). constants at the dopamine D2, D4, and 5-HT2A receptors. Recently, therefore, this dependence of the neurolep­ tic dissociation constant on the radioligand was studied in more detail (Seeman and Van Tol 1995; Seeman 1995b). It was found that the neuroleptic dissociation THE NEUROLEPTIC DISSOCIATION constant depended on the tissue:buffer partition coeffi­ CONSTANT VARIES WITH THE TISSUE: cient of the radioligand. A similar finding has recently BUFFER PARTITION OF THE RADIOLIGAND been made by Durcan et al. (1995). For example, clozapine at the D2 receptor revealed a To derive the therapeutic receptor-blocking concentra­ dissociation constant of 390 nM with [3H]-nemonapride, tions of neuroleptics and to assess the different hypoth­ 186 nM with [3H]-spiperone, and 83 nM with [3H]-raclo­ eses for atypical neuroleptic action, it is essential to use pride. Haloperidol also had a dissociation constant of 3 neuroleptic dissociation constants that have been mea­ 9.6 nM at dopamine D2 receptors using [ H]-nem­ sured with the minimum experimental artifacts. onapride, 2.7 nM using [3H]-spiperone, and 0.67 nM us­ For example, it has been found that the dissociation ing [3H]-raclopride. These neuroleptic dissociation con­ constant of a neuroleptic (e.g. [3H]-spiperone) can range stants were related to the tissue:buffer partition coef­ from 30 pM up to 1,600 pM as the final concentration of ficients of the radioligands, as shown in Figures 1 and 2. tissue is increased (Seeman et al. 1984). Currently, how­ ever, the final concentrations of tissue in most laborato­ ries is kept very low to minimize tissue dependence. Although many other factors may also determine the THE RADIOLIGAND-INDEPENDENT dissociation constant of an antipsychotic drug at various DISSOCIATION CONSTANT receptors, the literature on this topic is not extensive. The pH, for example, determines not only the surface It is possible to eliminate the dependence of the neuro­ activities (Seeman and Bialy 1963) and the membrane: leptic dislocation constant on the radioligand and thereby buffer partition coefficients of neuroleptics (Seeman obtain the dissociation constant of the neuroleptic in the 1966a, 1966b; Seeman and Weinstein 1966; Seeman and absence of any competing radioligand. This may be Kwant 1969), but also the dissociation constant of the done by extrapolating the relation shown (Figure 2) neuroleptic at the dopamine D2 receptor (e.g., sulpiride; down to either unity or zero partition, yielding an inter­ Presland and Strange 1991). The surface charge of the cept. This intercept represents the dissociation constant NEUROPSYCHOPHARMACOLOGY 1997-VOL. 16, NO. 2 Atypical Neuroleptics and DA D2 and D4 Receptors 95 3000 2500 /~ .... ,.--~ Q) K = 1.2 nM - 2000 <;>)('I - 'o c.. '°~- K = 7.3 nM Cl 1500 1000 HUMAN D2 LONG 0.01 0.1 10 100 1000 10µM nM Haloperidol S-Sulpiride 15 10 P = 14 pmol/g 5 nM El 0 E C. 0 "C 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 C :J [3H]Spiperone, nM 0 Ill 30 0 20 pmol/g 10 • e~\\\C nM 1 2 3 4 5 6 7 [3H]Raclopride, nM Figure 1. Top, a representative experiment showing that the haloperidol dissociation constant (or inhibition constant) was high (7.3 nM) when competing versus PH]-nemonapride, but lower when competing versus PH]-spiperone (2.8 nM) and even lower when using [3H]-raclopride (1.2 nM). These K values were derived by the Cheng-Prusoff (1973) equation, using the appropriate KJ value for each ['HJ-ligand (adapted from Seeman and Van Tol 1995). (The Hill coefficient for the competi­ tion of haloperidol with each radioligand was not significantly different from unity).
Load more

Recommended publications
  • Granisetron "Vianex"
    EU‐RISK MANAGEMENT PLAN GRANISETRON VIANEX® 1 MG/ML, SOLUTION FOR INJECTION/ INFUSION precautionary measure, breast‐feeding should not be advised during treatment with Granisetron “Vianex”. Legal Status: Prescription only product. VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology Nausea and vomiting associated with chemotherapy and radiotheraphy: One of the most distressing symptoms for patients undergoing both surgery and chemotherapy is nausea and vomiting. These symptoms have a significant impact on quality of life and can lead to malnutrition, inability to respond to treatment and an increased length of hospitalization. Emesis is more commonly associated with chemotherapeutic agents; however, radiation‐induced nausea and vomiting (RINV) can affect a significant proportion of patients, depending on the treated area, dose fractionation, and volume of radiotherapy. The relative risk for developing nausea and vomiting with chemotherapy ranges from 30 to 90% and is dependent upon the chemotherapeutic agent used. Relative risk for nausea and vomiting with radiation therapy is approximately 40%.2,3,4,5 Post‐operative nausea and vomiting Postoperative nausea and vomiting (PONV) is a major source of patient dissatisfaction and is the leading cause of discharge delays and unanticipated postsurgical hospital admissions. In the absence of pharmacological treatment, the rate of PONV is approximately 30% in general population, and can be as high as 70% in patients at highest risk. Several risk factors as surgery type, female gender, non‐smoker status, history of postoperative nausea and vomiting or motion sickness and post‐operative opioid use have been acknowledged. Additionally, post‐ operative vomiting (POV) occurs twice as frequently in children as in adults, increasing until puberty and then decreasing to adult incidence rates.
    [Show full text]
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • Product List March 2019 - Page 1 of 53
    Wessex has been sourcing and supplying active substances to medicine manufacturers since its incorporation in 1994. We supply from known, trusted partners working to full cGMP and with full regulatory support. Please contact us for details of the following products. Product CAS No. ( R)-2-Methyl-CBS-oxazaborolidine 112022-83-0 (-) (1R) Menthyl Chloroformate 14602-86-9 (+)-Sotalol Hydrochloride 959-24-0 (2R)-2-[(4-Ethyl-2, 3-dioxopiperazinyl) carbonylamino]-2-phenylacetic 63422-71-9 acid (2R)-2-[(4-Ethyl-2-3-dioxopiperazinyl) carbonylamino]-2-(4- 62893-24-7 hydroxyphenyl) acetic acid (r)-(+)-α-Lipoic Acid 1200-22-2 (S)-1-(2-Chloroacetyl) pyrrolidine-2-carbonitrile 207557-35-5 1,1'-Carbonyl diimidazole 530-62-1 1,3-Cyclohexanedione 504-02-9 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol acetate 839705-03-2 1-[2-Amino-1-(4-methoxyphenyl) ethyl] cyclohexanol Hydrochloride 130198-05-9 1-[Cyano-(4-methoxyphenyl) methyl] cyclohexanol 93413-76-4 1-Chloroethyl-4-nitrophenyl carbonate 101623-69-2 2-(2-Aminothiazol-4-yl) acetic acid Hydrochloride 66659-20-9 2-(4-Nitrophenyl)ethanamine Hydrochloride 29968-78-3 2,4 Dichlorobenzyl Alcohol (2,4 DCBA) 1777-82-8 2,6-Dichlorophenol 87-65-0 2.6 Diamino Pyridine 136-40-3 2-Aminoheptane Sulfate 6411-75-2 2-Ethylhexanoyl Chloride 760-67-8 2-Ethylhexyl Chloroformate 24468-13-1 2-Isopropyl-4-(N-methylaminomethyl) thiazole Hydrochloride 908591-25-3 4,4,4-Trifluoro-1-(4-methylphenyl)-1,3-butane dione 720-94-5 4,5,6,7-Tetrahydrothieno[3,2,c] pyridine Hydrochloride 28783-41-7 4-Chloro-N-methyl-piperidine 5570-77-4
    [Show full text]
  • Prevalence and Type of Potential Pharmacokinetic Drug-Drug Interactions in Old Aged Psychiatric Patients
    Contemporary Behavioral Health Care Research Article ISSN: 2058-8690 Prevalence and type of potential pharmacokinetic drug- drug interactions in old aged psychiatric patients Gudrun Hefner1,2*, Stefan Unterecker3, Nagia Ben-Omar4, Margarete Wolf4, Tanja Falter2, Christoph Hiemke1 and Ekkehard Haen4 1Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Germany 2Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany 3Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Germany 4Department of Psychiatry and Psychotherapy, University of Regensburg, Germany Abstract Purpose: The number of prescribed drugs increases with age, and resulting polypharmacy bears the risk of drug-drug interactions (DDI). We assessed the prevalence and type of cytochrome P450 (CYP) associated pharmacokinetic DDI that were considered as clinically relevant in elderly psychiatric patients under conditions of every day pharmacotherapy. Methods: For retrospective analysis a large therapeutic drug monitoring (TDM) data base was used. Patients included were elderly in- and outpatients, aged ≥ 65 years with a psychiatric disorder for whom serum level measurements of a psychotropic drug had been requested. Medication data were examined for co-prescription of clinically relevant CYP inhibitors or inducers and drugs that are substrates of these enzymes (victim drugs). Results: Data from 1243 patients (65.3% female) with a mean (± standard deviation) age of 73 ± 6 years were available for analysis. Mean number of prescribed drugs was 5.3 ± 3.4 per patient. Moderate (n=189, 73.8%) or strong (n=67, 26.2%) CYP inhibitors or inducers were prescribed in 18.9% of all patients. Most frequently prescribed CYP inhibitors were duloxetine (CYP2D6 inhibitor, n=73, 31.7%), melperone (CYP2D6 inhibitor, n=63, 27.4%) and omeprazole (CYP2C19 inhibitor, n=20, 8.7%).
    [Show full text]
  • The Effect of 5-HT1A Receptor Antagonist on Reward-Based
    The Journal of Physiological Sciences (2019) 69:1057–1069 https://doi.org/10.1007/s12576-019-00725-1 ORIGINAL PAPER The efect of 5‑HT1A receptor antagonist on reward‑based decision‑making Fumika Akizawa1 · Takashi Mizuhiki1,2 · Tsuyoshi Setogawa1,2 · Mai Takafuji1 · Munetaka Shidara1,2 Received: 5 July 2019 / Accepted: 27 October 2019 / Published online: 8 November 2019 © The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2019 Abstract When choosing the best action from several alternatives, we compare each value that depends on the balance between beneft and cost. Previous studies have shown that animals and humans with low brain serotonin (5-HT) level tend to choose smaller immediate reward. We used a decision-making schedule task to investigate whether 5-HT1A receptor is responsible for the decisions related to reward. In this task, the monkeys chose either of two diferent alternatives that were comprised of 1–4 drops of liquid reward (beneft) and 1–4 repeats of a color discrimination trial (workload cost), then executed the chosen schedule. By the administration of 5-HT1A antagonist, WAY100635, the choice tendency did not change, however, the sen- sitivity to the amount of reward in the schedule part was diminished. The 5-HT1A could have a role in maintaining reward value to keep track with the promised reward rather than modulating workload discounting of reward value. Keywords 5-HT1A · Value discounting · WAY100635 · Decision-making · Workload · Rhesus monkey Introduction comprises an iteration of simple color discriminations. The monkey can choose one of two diferent schedules to earn Whenever we choose an option from two or more alterna- promised reward.
    [Show full text]
  • Hypochlorous Acid Handling
    Hypochlorous Acid Handling 1 Identification of Petitioned Substance 2 Chemical Names: Hypochlorous acid, CAS Numbers: 7790-92-3 3 hypochloric(I) acid, chloranol, 4 hydroxidochlorine 10 Other Codes: European Community 11 Number-22757, IUPAC-Hypochlorous acid 5 Other Name: Hydrogen hypochlorite, 6 Chlorine hydroxide List other codes: PubChem CID 24341 7 Trade Names: Bleach, Sodium hypochlorite, InChI Key: QWPPOHNGKGFGJK- 8 Calcium hypochlorite, Sterilox, hypochlorite, UHFFFAOYSA-N 9 NVC-10 UNII: 712K4CDC10 12 Summary of Petitioned Use 13 A petition has been received from a stakeholder requesting that hypochlorous acid (also referred 14 to as electrolyzed water (EW)) be added to the list of synthetic substances allowed for use in 15 organic production and handling (7 CFR §§ 205.600-606). Specifically, the petition concerns the 16 formation of hypochlorous acid at the anode of an electrolysis apparatus designed for its 17 production from a brine solution. This active ingredient is aqueous hypochlorous acid which acts 18 as an oxidizing agent. The petitioner plans use hypochlorous acid as a sanitizer and antimicrobial 19 agent for the production and handling of organic products. The petition also requests to resolve a 20 difference in interpretation of allowed substances for chlorine materials on the National List of 21 Allowed and Prohibited Substances that contain the active ingredient hypochlorous acid (NOP- 22 PM 14-3 Electrolyzed water). 23 The NOP has issued NOP 5026 “Guidance, the use of Chlorine Materials in Organic Production 24 and Handling.” This guidance document clarifies the use of chlorine materials in organic 25 production and handling to align the National List with the November, 1995 NOSB 26 recommendation on chlorine materials which read: 27 “Allowed for disinfecting and sanitizing food contact surfaces.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2010/0179214 A1 Dubé Et Al
    US 20100179214A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0179214 A1 Dubé et al. (43) Pub. Date: Jul. 15, 2010 (54) DOXEPIN TRANS ISOMERS AND SOMERC continuation-in-part of application No. 1 1/804,720, MIXTURES AND METHODS OF USING THE filed on May 18, 2007. SAME TO TREAT SLEEP DSORDERS (60) Provisional application No. 60/898,378, filed on Jan. (75) Inventors: Susan E. Dubé, Carlsbad, CA (US); 30, 2007, provisional application No. 60/801,824, Neil B. Kavey, Chappaqua, NY filed on May 19, 2006, provisional application No. (US) 60/833,319, filed on Jul 25, 2006. Correspondence Address: KNOBBE MARTENS OLSON & BEAR LLP Publication Classification 2040 MAINSTREET, FOURTEENTH FLOOR (51) Int. Cl. IRVINE, CA 92.614 (US) A63L/335 (2006.01) A6IP 25/20 (2006.01) (73) Assignee: SOMAXON PHARMACEUTICALS, INC., (52) U.S. Cl. ........................................................ S14/450 San Diego, CA (US) (21) Appl. No.: 12/535,623 (57) ABSTRACT The invention relates to use of the trans-(E) isomer or iso (22) Filed: Aug. 4, 2009 meric mixtures containing specified ratios of the trans-(E) and cis-(Z) isomers of doxepin, metabolites of doxepin, phar Related U.S. Application Data maceutically-acceptable salts of doxepin and prodrugs of the (63) Continuation-in-part of application No. 12/022,788, same; compositions containing the same, for the treatment of filed on Jan. 30, 2008, now abandoned, which is a sleep disorders US 2010/0179214 A1 Jul. 15, 2010 DOXEPIN TRANS ISOMERS AND SOMERC brings scrutiny from the Drug Enforcement Administration MIXTURES AND METHODS OF USING THE and other regulatory bodies, and requires registration and SAME TO TREAT SLEEP DSORDERS administrative controls in physicians offices.
    [Show full text]
  • Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: a PET Study in Conscious Monkeys
    Neuropsychopharmacology (2013) 38, 2666–2674 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys 1 1 1 1 1 Shigeyuki Yamamoto , Hiroyuki Ohba , Shingo Nishiyama , Norihiro Harada , Takeharu Kakiuchi , 1 ,2 Hideo Tsukada and Edward F Domino* 1 2 Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Japan; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys 11 underwent four positron emission tomography measurements with [ C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzoni- 11 trile ([ C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a 11 dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [11C]DASB. No significant changes were observed in either 5-HT -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased 1A serotonin levels in the extracellular fluid of the prefrontal cortex.
    [Show full text]
  • Selective Labeling of Serotonin Receptors Byd-[3H]Lysergic Acid
    Proc. Nati. Acad. Sci. USA Vol. 75, No. 12, pp. 5783-5787, December 1978 Biochemistry Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate (ergots/hallucinogens/tryptamines/norepinephrine/dopamine) PATRICIA M. WHITAKER AND PHILIP SEEMAN* Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8 Communicated by Philip Siekevltz, August 18,1978 ABSTRACT Since it was known that d-lysergic acid di- The objective in this present study was to improve the se- ethylamide (LSD) affected catecholaminergic as well as sero- lectivity of [3H]LSD for serotonin receptors, concomitantly toninergic neurons, the objective in this study was to enhance using other drugs to block a-adrenergic and dopamine receptors the selectivity of [3HJISD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of (cf. refs. 36-38). We then compared the potencies of various a combination of 50 nM each of phentolamine (adde to pre- drugs on this selective [3H]LSD binding and compared these clude the binding of [3HJLSD to a-adrenoceptors), apmo ie, data to those for the high-affinity binding of [3H]serotonin and spiperone (added to preclude the binding of [3H[LSD to (39). dopamine receptors), it was found by Scatchard analysis that the total number of 3H sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catechol- METHODS amine-blocking drugs. The IC50 values (concentrations to inhibit Preparation of Membranes. Calf brains were obtained fresh binding by 50%) for various drugs were tested on the binding of [3HLSD in the presence of 50 nM each of apomorphine (A), from the Canada Packers Hunisett plant (Toronto).
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Pharmacotherapy, Drug-Drug Interactions and Potentially
    medRxiv preprint doi: https://doi.org/10.1101/2021.03.31.21254518; this version posted April 6, 2021. 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 . Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders Jan Wolff1,2,3, Pamela Reißner4, Gudrun Hefner5, Claus Normann2, Klaus Kaier6, Harald Binder6, Christoph Hiemke7, Sermin Toto8, Katharina Domschke2, Michael Marschollek1, Ansgar Klimke4,9 1 Peter L. Reichertz Institute for Medical Informatics of TU Braunschweig and Hannover Medical School, Germany. 2 Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 3 Evangelical Foundation NeuerKerode, Germany. 4 Vitos Hochtaunus, Friedrichsdorf, Germany. 5 Vitos Clinic for Forensic Psychiatry, Eltville, Germany 6 Institute of Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. 7 Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Germany. 8 Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Germany. 9 Heinrich-Heine-University Düsseldorf, Germany. ___ Correspondence Dr. Jan Wolff, Peter L. Reichertz Institute for Medical Informatics of TU Braunschweig and Hannover Medical School, Hannover, Germany. Address: Karl- Wiechert-Allee 3, 30625 Hannover. Email: [email protected], wolff.jan@mh- hannover.de, ORCID: https://orcid.org/0000-0003-2750-0606 Key words (MeSH) Depression, Polypharmacy, Antidepressants, Hospitals, Drug Interactions, Psychiatry NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
    [Show full text]
  • Appendix 13C: Clinical Evidence Study Characteristics Tables
    APPENDIX 13C: CLINICAL EVIDENCE STUDY CHARACTERISTICS TABLES: PHARMACOLOGICAL INTERVENTIONS Abbreviations ............................................................................................................ 3 APPENDIX 13C (I): INCLUDED STUDIES FOR INITIAL TREATMENT WITH ANTIPSYCHOTIC MEDICATION .................................. 4 ARANGO2009 .................................................................................................................................. 4 BERGER2008 .................................................................................................................................... 6 LIEBERMAN2003 ............................................................................................................................ 8 MCEVOY2007 ................................................................................................................................ 10 ROBINSON2006 ............................................................................................................................. 12 SCHOOLER2005 ............................................................................................................................ 14 SIKICH2008 .................................................................................................................................... 16 SWADI2010..................................................................................................................................... 19 VANBRUGGEN2003 ....................................................................................................................
    [Show full text]