DOCSLIB.ORG

Dopamine D2 Receptor Gene Polymorphisms and Response to Cabergoline Therapy in Patients with Prolactin-Secreting Pituitary Adenomas

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dopamine D2 Receptor Gene Polymorphisms and Response to Cabergoline Therapy in Patients with Prolactin-Secreting Pituitary Adenomas The Pharmacogenomics Journal (2008) 8, 357–363 & 2008 Nature Publishing Group All rights reserved 1470-269X/08 $30.00 www.nature.com/tpj ORIGINAL ARTICLE Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas M Filopanti1, AM Barbieri1, Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and 1 2 3 tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) AR Angioni ,AColao , V Gasco , by binding type 2 dopamine receptor (DRD2). The mechanisms responsible 3 4 4 S Grottoli , A Peri , S Baglioni , for resistance to CB remain largely unknown. To assess the association of MF Fustini5, F Pigliaru6, DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T PD Monte7, G Borretta8, genotypes were determined in a cross-sectional retrospective study, B Ambrosi9, ML Jaffrain-Rea10, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ 11 12 between patients and 212 healthy subjects. Conversely, NcoI-T allele M Gasperi , S Brogioni , frequency was higher in resistant rather than responsive patients, considering S Cannavo` 13, G Mantovani1, both PRL normalization (56.6 vs 45.3%, P ¼ 0.038) and tumor shrinkage P Beck-Peccoz1, A Lania1 and (70.4 vs 41.4%, P ¼ 0.006). Finally, [TaqIA1À/TaqIB1À/HphITÀ/NcoITÀ] A Spada1 haplotype was found in 34.5% of patients normalizing PRL with p3 mg/ week of CB vs 11.3% of resistants (P ¼ 0.021). In conclusion, resistance to CB 1Department of Medical Sciences, University of Milan, was associated with DRD2 NcoI-T þ allele, consistent with evidence Endocrine and Diabetes Unit Fondazione Ospedale suggesting that this variant may lead to reduction and instability of DRD2 Maggiore IRCCS, Milan, Italy; 2Department of mRNA or protein. Molecular and Clinical Endocrinology and Oncology, The Pharmacogenomics Journal (2008) 8, 357–363; doi:10.1038/tpj.2008.1; Federico II University of Naples, Naples, Italy; 3Division of Endocrinology and Metabolism, published online 11 March 2008 Department of Internal Medicine, University of Turin, Turin, Italy; 4Endocrine Unit, Department of Clinical Keywords: prolactinomas; cabergoline; polymorphisms; DRD2 Physiopathology, Center for Research, Transfer and High Education DENOThe, University of Florence, Florence, Italy; 5Endocrinology Unit, Department of Medicine, Ospedale Bellaria, Bologna, Italy; 6Endocrinology, Department of Medical Sciences ‘M. Aresu’, University of Cagliari, Cagliari, Italy; 7Unit of Endocrinology, Galliera Hospital, Genoa, Italy; Introduction 8Endocrinology Unit, Santa Croce Hospital, Cuneo, Italy; 9Endocrinology Unit, Department of Medical Prolactin-secreting pituitary adenomas (PRL-omas) are rare and well-differen- and Surgical Sciences, University of Milan, IRCCS 10 tiated tumors constituted by lactotroph cells with an estimated incidence of 6–10 Policlinico San Donato, Milan, Italy; Department of 1 Experimental Medicine, University of L’Aquila and cases per million per year. The first-choice treatment of patients with PRL-omas Neuromed IRCCS, Pozzilli, Italy; 11Chair of is the dopamine agonist cabergoline (CB), a lysergic acid amide derivative, which Endocrinology, University of Molise, Campobasso, is a potent type 2 dopamine receptor (DRD2) agonist and causes less side effects 12 Italy; Department of Endocrinology, University of and a better pharmacological profile than other dopamine agonists. Resistance to Pisa, Pisa, Italy and 13Department of Medicine and Pharmacology, University of Messina, Messina, Italy CB, defined as failure to normalize PRL levels and/or to reduce tumor size, is reported in 10–15% of patients with PRL-omas.2 Reduction of dopaminergic Correspondence: binding sites, decreased expression of DRD2 mRNA and a relative decrease in Gai Professor A Spada, University of Milan, expression have been described in resistant PRL-omas, as well as reduced levels of Department of Medical Sciences, Endocrine the short receptor isoform.3–5 Finally, no mutations in the DRD2 gene have been and Diabetes Unit, Pad. Granelli, Via Francesco 6 Sforza 35, Milan 20122, Italy; so far described in PRL-omas resistant to medical treatment. E-mail: [email protected] Multiple alternative splicing, including that occurring in exon 6 and generating the two major long and short isoforms, have been described for the Received 18 July 2007; revised 12 December 7,8 2007; accepted 20 December 2007; published DRD2. Moreover, there are several single nucleotide polymorphisms of the online 11 March 2008 DRD2 gene that have mostly synonymous changes. Due to the critical role of DRD2 polymorphisms and response to cabergoline in PRL-omas M Filopanti et al 358 dopaminergic activity in the central nervous system, several heterozygotes, forming TaqIA1þ , TaqIB1þ , HphITþ and studies examined the association between common poly- NcoITþ groups, respectively. morphisms of the DRD2 gene and behavioral traits, No association between DRD2 polymorphisms and sex, psychiatric and neurological diseases, such as schizophrenia, age at diagnosis and PRL levels was observed in patients with alcoholism, smoking, opioids and polysubstance abuse, and PRL-oma (Table 2). PRL Z-scores did not significantly differ susceptibility to migraine.9–14 Accordingly, in vivo evidence between genotypes (TaqIA1À 275.4±440.0 vs A1 þ supporting the potential functional significance of DRD2 550.0±280.5, P ¼ 0.187; TaqIB1À 550.3±486.7 vs B1 þ variants has been accumulating. In particular, previous 267.4±442.3, P ¼ 0.176; HphITÀ 529.5±292.2 vs studies reported the association of DRD2 TaqIA,TaqIB TÀ 1171.7±1235.4, P ¼ 0.262; NcoITÀ 506.5±432.3 vs and NcoI polymorphisms with modifications in D2 receptor T þ 1328.0±753.6, P ¼ 0.592). Conversely, patients with binding and expression in human central nervous system, microadenoma showed a strong linkage disequilibrium particularly in the striatum.15–18 between TaqIA1À and HphITÀ polymorphisms (D0 ¼ 1.0, The aim of this study was to assess the possible association r2 ¼ 0.879), which was not present in patients with macro- between four common DRD2 gene polymorphisms (that is, adenoma. TaqI A1/A2, TaqI B1/B2, HphI G/T and NcoI C/T) and the efficacy of CB treatment in patients with PRL-oma. Genotype analysis in patients with PRL-omas and sensitivity to CB Results treatment When considering patients who achieved PRL normaliza- Clinical data tion and tumor-size reduction under CB treatment (from 0.5 Two hundred and three patients with PRL-omas (98 male to 3 mg/week), no association between DRD2 polymorph- and 105 female, mean age at diagnosis 36.6±15.0 years) isms and the effective CB dosage was observed. Similarly, no were enrolled in this retrospective cross-sectional study. As it association between TaqIA,TaqI B and HphI polymorphisms is known that the size of the tumor is one of the major and resistance to CB in terms of PRL and tumor size was determinants of PRL levels, the study included a similar found (Table 3). By contrast, the prevalence of NcoI number of patients with either micro- or macro-PRL-oma genotype was different in patients resistant to CB treatment (adenoma size o10 mm or X10 mm, respectively) consecu- in comparison with those who were responsive. In fact, NcoI tively seen by the different centers. Subsequently, about half T þ allele was identified in 56.6% (12/22) of patients (50.3%) of the patients had a macroadenoma. All patients resistant to CB and 45.3% (84/181) of those normalizing at had a clinical and hormonal reevaluation every 3–4 months CB p3 mg/week (Fisher’s exact test, P ¼ 0.038) (Table 3). In and magnetic resonance imaging every 6–9 months. During the group of patients with NcoI T allele, TT homozygotes follow-up (range: 18–38 months), the mean lowest dosage of were 36% in responsive subjects vs 50% in resistants and TC CB required for PRL normalization and reduction of the heterozygotes were 9 vs 4%, respectively. tumor size was 1.40±1.13 mg/week, 45.3% patients requir- This association was also found, considering the tumor ing o1 mg/week. Twenty-two (10.8%) patients failed to shrinkage in response to CB, as NcoITþ variant was present normalize PRL levels with CB at the dosage of 43 mg/week in 70.4% of patients (12/17) who did not reach a 430% after 3–4 months follow-up and were considered resistant. In tumor-size reduction at CB p3 mg/week vs 41.4% (77/186) this subset, 54.6% of patients were males, 68.2% had a in the responsive group (Fisher’s exact test, P ¼ 0.006) (Table macroadenoma and the median PRL was 452 ng/ml (inter- 3). In the set of NcoI T allele carriers, TT homozygotes were quartile range 257–12 230). Seventeen (8.4%) patients did 35% in responsive patients vs 65% in resistants, and TC not reduce tumor size at CB 43 mg/week. A discrepancy heterozygotes were 7 vs 6%, respectively. between hormonal and tumor size responses was observed A multivariate logistic regression analysis has been carried in five patients with macroadenoma (three males and two out using backward method, considering failure to normal- females) in whom 43 mg/week of CB induced a tumor-size ize PRL levels with CB at the dosage of 43 mg/week as reduction from 60 to 75% without normalizing PRL levels. dependent variable and with the following predictors: TaqI The increase of CB dosage to 4, 4.5, 5 and 9 mg/week in 17, A þ , TaqIBþ , Hph T þ, NcoITþ, PRL levels, presence of 2, 2 and 1 patient, respectively, did not overcome the macroadenoma and age at diagnosis. Only NcoITþ resistance in terms of PRL normalization and tumor-size genotype was a significant predictor of the unsuccessful reduction in any patient. normalization of PRL by CB therapy (odds ratio 5.181, 95% confidence interval 1.369–19.1645, P ¼ 0.015).
Load more

Recommended publications
  • 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]
  • 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]
  • Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss
    Supplemental Material can be found at: /content/suppl/2020/12/18/73.1.202.DC1.html 1521-0081/73/1/202–277$35.00 https://doi.org/10.1124/pharmrev.120.000056 PHARMACOLOGICAL REVIEWS Pharmacol Rev 73:202–277, January 2021 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: MICHAEL NADER Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss Antonio Inserra, Danilo De Gregorio, and Gabriella Gobbi Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada Abstract ...................................................................................205 Significance Statement. ..................................................................205 I. Introduction . ..............................................................................205 A. Review Outline ........................................................................205 B. Psychiatric Disorders and the Need for Novel Pharmacotherapies .......................206 C. Psychedelic Compounds as Novel Therapeutics in Psychiatry: Overview and Comparison with Current Available Treatments . .....................................206 D. Classical or Serotonergic Psychedelics versus Nonclassical Psychedelics: Definition ......208 Downloaded from E. Dissociative Anesthetics................................................................209 F. Empathogens-Entactogens . ............................................................209
    [Show full text]
  • Dopamine D2 Receptors in the Cerebral Cortex
    Proc. Nati. Acad. Sci. USA Vol. 86, pp. 6412-6416, August 1989 Neurobiology Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3Hlraclopride (raclopride binding/neostriatum/rat/monkey) MICHAEL S. LIDOW*t, PATRICIA S. GOLDMAN-RAKIC*, PASKO RAKIC*, AND ROBERT B. INNIS*f Section of *Neuroanatomy and tDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT 06510 Contributed by Pasko Rakic, May 17, 1989 ABSTRACT An apparent involvement of dopamine in the MATERIALS AND METHODS regulation of cognitive functions and the recognition of a widespread dopaminergic innervation of the cortex have fo- Tissue was obtained from three adult rhesus monkeys cused attention on the identity of cortical dopamine receptors. (Macaca mulatta): one male and two females. The animals However, only the presence and distribution of dopamine DI were anesthesized with sodium pentobarbital (40 mg/kg) and receptors in the cortex have been well documented. Compa- perfused with ice-cold phosphate-buffered saline followed by rable information on cortical D2 sites is lacking. We report here 0.1% paraformaldehyde (9; 15). The cerebral cortex and the results of binding studies in the cortex and neostriatum of neostriatum were rapidly removed and immersed in isopen- rat and monkey using the D2 selective antagonist [3H]raclo- tane at -700C for 5 min before storing at -800C until use. For pride. In both structures [3H]raclopride bound in a sodium- competition studies tissue was pooled from several neocor- dependent and saturable manner to a single population of sites tical areas. However, saturation studies were conducted on with pharmacological profiles of dopamine D2 receptors.
    [Show full text]
  • Metabolic Changes in the Rodent Brain After Acute Administration of Salvinorin a Jacob M
    B Academy of Molecular Imaging, 2009 Mol Imaging Biol (2009) 11:137Y143 Published Online: 9 January 2009 DOI: 10.1007/s11307-008-0192-x BRIEF ARTICLE Metabolic Changes in the Rodent Brain after Acute Administration of Salvinorin A Jacob M. Hooker,1 Vinal Patel,1 Shiva Kothari,1 Wynne K. Schiffer1 Medical Department, Brookhaven National Laboratory, Upton, NY, 11973, USA Abstract Purpose: Salvinorin A (SA) is a potent and highly selective kappa-opioid receptor (KOR) agonist with rapid kinetics and commensurate behavioral effects; however, brain regions associated with these effects have not been determined. Procedures: Freely moving adult male rats were given SA intraperitoneally during uptake and trapping of the brain metabolic radiotracer, 2-deoxy-2-[F-18]fluoro-D-glucose (FDG), followed by image acquisition in a dedicated animal positron emission tomography (PET) system. Age-matched control animals received vehicle treatment. Animal behavior during FDG uptake was recorded digitally and later analyzed for locomotion. Group differences in regional FDG uptake normalized to whole brain were determined using Statistical Parametric Mapping (SPM) and verified by region of interest (ROI) analysis. Results: SA-treated animals demonstrated significant increases in FDG uptake compared to controls in several brain regions associated with the distribution of KOR such as the periaqueductal grey, bed nucleus of the stria terminalis and the cerebellar vermis, as well as in the hypothalamus. Significant bilateral activations were also observed in the auditory, sensory, and frontal cortices. Regional decreases in metabolic demand were observed bilaterally in the dorsolateral striatum and hippocampus. Locomotor activity did not differ between SA and vehicle during FDG uptake.
    [Show full text]
  • Interaction of Mephedrone with Dopamine and Serotonin Targets in Rats José Martínez-Clemente, Elena Escubedo, David Pubill, Jorge Camarasa⁎
    NEUPSY-10409; No of Pages 6 European Neuropsychopharmacology (2011) xx, xxx–xxx www.elsevier.com/locate/euroneuro Interaction of mephedrone with dopamine and serotonin targets in rats José Martínez-Clemente, Elena Escubedo, David Pubill, Jorge Camarasa⁎ Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), University of Barcelona, 08028 Barcelona, Spain Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain Received 20 May 2011; received in revised form 3 July 2011; accepted 6 July 2011 KEYWORDS Abstract Mephedrone; Dopamine; Introduction: We described a first approach to the pharmacological targets of mephedrone (4- Serotonin methyl-methcathinone) in rats to establish the basis of the mechanism of action of this drug of abuse. Experimental procedures: We performed in vitro experiments in isolated synaptosomes or tissue membrane preparations from rat cortex or striatum, studying the effect of mephedrone on monoamine uptake and the displacement of several specific radioligands by this drug. Results: In isolated synaptosomes from rat cortex or striatum, mephedrone inhibited the uptake of serotonin (5-HT) with an IC50 value lower than that of dopamine (DA) uptake (IC50 =0.31±0.08 and 0.97±0.05 μM, respectively). Moreover, mephedrone displaced competitively both [3H] paroxetine and [3H]WIN35428 binding in a concentration-dependent manner (Ki values of 17.55± 0.78 μM and 1.53±0.47 μM, respectively), indicating a greater affinity for DA than for 5-HT membrane transporters. The affinity profile of mephedrone for the 5-HT2 and D2 receptors was assessed by studying [3H]ketanserin and [3H] raclopride binding in rat membranes. Mephedrone showed a greater affinity for the 5-HT2 than for the D2 receptors.
    [Show full text]
  • Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans
    molecules Review Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans Paul Cumming 1,2,* , Milan Scheidegger 3 , Dario Dornbierer 3, Mikael Palner 4,5,6 , Boris B. Quednow 3,7 and Chantal Martin-Soelch 8 1 Department of Nuclear Medicine, Bern University Hospital, CH-3010 Bern, Switzerland 2 School of Psychology and Counselling, Queensland University of Technology, Brisbane 4059, Australia 3 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, CH-8032 Zurich, Switzerland; [email protected] (M.S.); [email protected] (D.D.); [email protected] (B.B.Q.) 4 Odense Department of Clinical Research, University of Southern Denmark, DK-5000 Odense, Denmark; [email protected] 5 Department of Nuclear Medicine, Odense University Hospital, DK-5000 Odense, Denmark 6 Neurobiology Research Unit, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark 7 Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, CH-8058 Zurich, Switzerland 8 Department of Psychology, University of Fribourg, CH-1700 Fribourg, Switzerland; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Hallucinogens are a loosely defined group of compounds including LSD, N,N- dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), Citation: Cumming, P.; Scheidegger, which can evoke intense visual and emotional experiences. We are witnessing a renaissance of re- M.; Dornbierer, D.; Palner, M.; search interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. Quednow, B.B.; Martin-Soelch, C. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and Molecular and Functional Imaging ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or Studies of Psychedelic Drug Action in single photon emission computer tomography (SPECT).
    [Show full text]
  • Variations in the Human Pain Stress Experience Mediated by Ventral and Dorsal Basal Ganglia Dopamine Activity
    The Journal of Neuroscience, October 18, 2006 • 26(42):10789–10795 • 10789 Behavioral/Systems/Cognitive Variations in the Human Pain Stress Experience Mediated by Ventral and Dorsal Basal Ganglia Dopamine Activity David J. Scott,1 Mary M. Heitzeg,1 Robert A. Koeppe,2 Christian S. Stohler,3 and Jon-Kar Zubieta1,2 1Department of Psychiatry and Molecular and Behavioral Neuroscience Institute and 2Department of Radiology, The University of Michigan, Ann Arbor, Michigan 48109-0720, and 3School of Dentistry, University of Maryland, Baltimore, Maryland 21201 In addition to its involvement in motor control and in encoding reward value, increasing evidence also implicates basal ganglia dopami- nergic mechanisms in responses to stress and aversive stimuli. Basal ganglia dopamine (DA) neurotransmission may then respond to environmental events depending on their saliency, orienting the subsequent responses of the organism to both positive and negative stimuli. Here we examined the involvement of DA neurotransmission in the human response to pain, a robust physical and emotional 11 stressor across species. Positron emission tomography with the DA D2 receptor antagonist radiotracer [ C]raclopride detected signifi- cant activation of DA release in dorsal and ventral regions of the basal ganglia of healthy volunteers. Activation of nigrostriatal (dorsal nucleus caudate and putamen) DA D2 receptor-mediated neurotransmission was positively associated with individual variations in subjective ratings of sensory and affective qualities of the pain. In contrast, mesolimbic (nucleus accumbens) DA activation, which may impact on both D2 and D3 receptors, was exclusively associated with variations in the emotional responses of the individual during the pain challenge (increases in negative affect and fear ratings).
    [Show full text]
  • SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action S
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2019/08/01/jpet.119.260281.DC1 1521-0103/371/1/1–14$35.00 https://doi.org/10.1124/jpet.119.260281 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 371:1–14, October 2019 Copyright ª 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action s Nina Dedic,1 Philip G. Jones,1 Seth C. Hopkins, Robert Lew, Liming Shao, John E. Campbell, Kerry L. Spear, Thomas H. Large, Una C. Campbell, Taleen Hanania, Emer Leahy, and Kenneth S. Koblan Sunovion Pharmaceuticals, Marlborough, Massachusetts (N.D., P.G.J., S.C.H., R.L., L.S., J.E.C., K.L.S., T.H.L., U.C.C., K.S.K.); and PsychoGenics, Paramus, New Jersey (T.H., E.L.) Received May 24, 2019; accepted July 10, 2019 Downloaded from ABSTRACT For the past 50 years, the clinical efficacy of antipsychotic amine-associated receptor 1 and 5-HT1A receptors is integral to medications has relied on blockade of dopamine D2 receptors. its efficacy. Based on the preclinical data and its unique Drug development of non-D2 compounds, seeking to avoid mechanism of action, SEP-856 is a promising new agent for the limiting side effects of dopamine receptor blockade, has the treatment of schizophrenia and represents a new pharma- jpet.aspetjournals.org failed to date to yield new medicines for patients.
    [Show full text]
  • WAY-100635 Binds to 5-HT1A Receptors and Provides a Higher Radioactive Signal Than [Carbonyl-11C]WAY-100635 in the Human Brain
    The PET Radioligand [carbonyl-11C]Desmethyl- WAY-100635 Binds to 5-HT1A Receptors and Provides a Higher Radioactive Signal Than [carbonyl-11C]WAY-100635 in the Human Brain Bengt Andre´e, MD, PhD1; Christer Halldin, PhD1; Victor W. Pike, PhD2; Roger N. Gunn, PhD2; Hans Olsson, MD1; and Lars Farde, MD, PhD1 1Psychiatry Section, Department of Clinical Neuroscience, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden; and 2MRC Cyclotron Unit, Hammersmith Hospital, Imperial College School of Medicine, London, United Kingdom nents. For 11C-WAY, small amounts of an additional labeled metabolite comigrated with reference desmethyl-WAY- 5-Hydroxytryptamine (serotonin)-1A (5-HT1A) receptors are of key interest in research on the pathophysiology and treat- 100635. Conclusion: The advantages of 11C-DWAY over 11C- ment of psychiatric disorders. The PET radioligand [carbonyl- WAY for research on central 5-HT1A receptors is supported by 11C]WAY-100635 (11C-WAY), where WAY-100635 is 3H-(N-(2- a significantly higher radioactivity signal at equipotent doses, (1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) providing improved imaging statistics and advantages in bio- cyclohexane-carboxamide, is commonly used for quantita- mathematic modeling and the preclusion of 11C-DWAY as a tion of 5-HT1A receptors in the human brain. The aim of this metabolite interfering with PET measurements. PET study was to compare 11C-WAY with the putative me- Key Words: brain; human; PET; 5-hydroxytryptamine-1A recep- tabolite and selective radioligand [carbonyl-11C]desmethyl- tors; WAY-100635; desmethyl-WAY-100635; kinetic modeling WAY-100635 (11C-DWAY). Methods: A PET examination was J Nucl Med 2002; 43:292–303 performed on each of 5 healthy male volunteers after intra- venous injection of 11C-WAY and 11C-DWAY on separate occasions.
    [Show full text]
  • A Mechanistic Account of Striatal Dopamine Function in Human Cognition: Psychopharmacological Studies with Cabergoline and Haloperidol
    Behavioral Neuroscience Copyright 2006 by the American Psychological Association 2006, Vol. 120, No. 3, 497–517 0735-7044/06/$12.00 DOI: 10.1037/0735-7044.120.3.497 A Mechanistic Account of Striatal Dopamine Function in Human Cognition: Psychopharmacological Studies With Cabergoline and Haloperidol Michael J. Frank Randall C. O’Reilly University of Arizona University of Colorado at Boulder The authors test a neurocomputational model of dopamine function in cognition by administering to healthy participants low doses of D2 agents cabergoline and haloperidol. The model suggests that DA dynamically modulates the balance of Go and No-Go basal ganglia pathways during cognitive learning and performance. Cabergoline impaired, while haloperidol enhanced, Go learning from positive rein- forcement, consistent with presynaptic drug effects. Cabergoline also caused an overall bias toward Go responding, consistent with postsynaptic action. These same effects extended to working memory and attentional domains, supporting the idea that the basal ganglia/dopamine system modulates the updating of prefrontal representations. Drug effects interacted with baseline working memory span in all tasks. Taken together, the results support a unified account of the role of dopamine in modulating cognitive processes that depend on the basal ganglia. Keywords: basal ganglia, dopamine, cognition, computational, psychopharmacology The basal ganglia (BG) participate in various aspects of cogni- Carter, Noll, & Cohen, 2003; Willcutt et al., 2005). Consequently, tion and
    [Show full text]
  • Diagnostic Imaging of Dopamine Receptors in Pituitary Adenomas
    European Journal of Endocrinology (2007) 156 S53–S56 ISSN 0804-4643 Diagnostic imaging of dopamine receptors in pituitary adenomas Wouter W de Herder, Ambroos E M Reijs1, Richard A Feelders, Maarten O van Aken, Eric P Krenning1, Aart-Jan van der Lely and Dik J Kwekkeboom1 Departments of Internal Medicine and Nuclear Medicine1, Erasmus MC, Rotterdam, The Netherlands (Correspondence should be addressed to W W de Herder who is now at the Sector of Endocrinology, Department of Internal Medicine, Erasmus MC, S-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; Email: [email protected]) Abstract Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using 123I-S-(K)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6- methoxybenzamide (123I-IBZM) and 123I-epidepride. 123I-epidepride is generally superior to 123I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, 123I-IBZM and 123I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with 11C-N-raclopride and 11C-N-methylspiperone. European Journal of Endocrinology 156 S53–S56 Introduction affinity D2 receptors on prolactinomas, some GH-, TSH- and ACTH-secreting tumours is the pharmacological Pituitary adenomas are subclassified according to basis for therapy with dopamine receptor agonist drugs, hormonal hypersecretion into clinically functioning and like the ergot-derived substances bromocriptine, pergo- clinically non-functioning.
    [Show full text]