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Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys

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Abstract

Rationale

Experimental evidence suggests that the differential behavioral effects of benzodiazepines depend on their relative actions at γ-aminobutyric acid type A (GABAA) receptors that contain either an α1, α2, α3, or α5 subunit.

Objectives

The present study was aimed at understanding the role of α3 subunit-containing GABAA (α3GABAA) receptors by examining the behavioral pharmacology of TP003 (4,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridine-3-yl]biphenyl-2-carbonitrile), which shows functional selectivity for α3GABAA receptors.

Methods

First, a conflict procedure was used to assess the anxiolytic-like effects of TP003 and a representative clinically available benzodiazepine. TP003 was also administered before daily periods of sucrose pellet availability to evaluate potential hyperphagic effects. In separate experiments, observable behavioral effects were used to assess the motor and sedative effects of TP003.

Results

Administration of TP003 produced robust anti-conflict effects without the rate-decreasing effects that were observed with the representative benzodiazepine. Unlike the reported effects of benzodiazepines, TP003 did not enhance palatable food consumption. However, increases in observable sleep-associated posture were induced by TP003, as were decreases in some species-typical behaviors (vocalization, locomotion, and environment-directed behaviors). When evaluated for its ability to induce a procumbent posture, TP003 failed to produce an effect.

Conclusions

Based on conflict and observation tests in monkeys, our results suggest that TP003 may have anxiolytic properties but lack ataxic, hyperphagic, and pronounced sedative effects characteristic of classical benzodiazepines. TP003 did induce myorelaxant-like effects and had relatively mild sedative effects. Collectively, these results suggest that α3GABAA receptors play an important role in the anxiolytic-like and motor effects of benzodiazepine-type drugs.

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References

  • Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, Ragan I, Kerby J, Street L, Carling R, Castro JL, Whiting P, Dawson GR, McKernan RM (2006) TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1, 2, 4-triazol-30ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4, 3-b]pyridazine], an agonist selective for α2 and α3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther 316:410–422

    Article  PubMed  CAS  Google Scholar 

  • Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22:5572–5580

    PubMed  CAS  Google Scholar 

  • Cooper SJ, Estall LB (1985) Behavioural pharmacology of food, water and salt intake in relation to drug actions at benzodiazepine receptors. Neurosci Biobehav Rev 9:5–19

    Article  PubMed  CAS  Google Scholar 

  • Cooper SJ, Ridley ET (2005) Abecarnil and palatability: taste reactivity in normal ingestion in male rats. Pharmacol Biochem Behav 81:517–523

    Article  PubMed  CAS  Google Scholar 

  • Crestani F, Löw K, Keist R, Mandelli M, Möhler H, Rudolph U (2001) Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol 59:442–445

    PubMed  CAS  Google Scholar 

  • Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Blüthmann H, Möhler H, Rudolph U (2002) Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci USA 99:8980–8985

    Article  PubMed  CAS  Google Scholar 

  • Dias R, Sheppard WF, Fradley RL, Garrett EM, Stanley JL, Tye SJ, Goodacre S, Lincoln RJ, Cook SM, Conley R, Hallett D, Humphries AC, Thompson SA, Wafford KA, Street LJ, Castro JL, Whiting PJ, Rosahl TW, Atack JR, McKernan RM, Dawson GR, Reynolds DS (2005) Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci 25:10682–10688

    Article  PubMed  CAS  Google Scholar 

  • Duke AN, Platt DM, Cook JM, Huang S, Yin W, Mattingly BA, Rowlett JK (2006) Enhanced sucrose pellet consumption induced by benzodiazepine-type drugs in squirrel monkeys: role of GABAA receptor subtypes. Psychopharmacology (Berl) 187:321–330

    Article  CAS  Google Scholar 

  • Fischer BD, Licata SC, Edwankar RV, Wang Z-J, Huang S, He X, Yu J, Zhou H, Johnson EM, Cook JM, Furtmüller R, Ramerstorfer J, Sieghart W, Roth BL, Majumder S, Rowlett JK (2010) Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure. Neuropharmacology 59:612–618

    Article  PubMed  CAS  Google Scholar 

  • Geller I, Seifter J (1962) The effects of mono-urethans, di-urethans and barbiturates on a punishment discrimination. J Pharmacol Exp Ther 136:284–288

    PubMed  CAS  Google Scholar 

  • Kleven MS, Koek W (1999) Effects of different classes of partial benzodiazepine agonists on punished and unpunished responding in pigeons. Psychopharmacology (Berl) 144:405–410

    Article  CAS  Google Scholar 

  • Kumar R, Palit G, Singh JR, Dhawan BN (1999) Comparative behavioural effects of benzodiazepine and non-benzodiazepine anxiolytics in rhesus monkeys. Pharmacol Res 39:437–444

    Article  PubMed  CAS  Google Scholar 

  • Licata SC, Platt DM, Cook JM, Sarma PV, Griebel G, Rowlett JK (2005) Contribution of GABAA receptor subtypes to the anxiolytic-like, motor, and discriminative stimulus effects of benzodiazepines: studies with the functionally selective ligand SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one]. J Pharmacol Exp Ther 313:1118–1125

    Article  PubMed  CAS  Google Scholar 

  • Licata SC, Platt DM, Cook JM, Van Linn ML, Rowlett JK (2009) Contribution of alpha1 subunit-containing gamma-aminobutyric acid (A) (GABA (A)) receptors to motor-impairing effects of benzodiazepines in squirrel monkeys. Psychopharmacology (Berl) 203:539–546

    Article  CAS  Google Scholar 

  • Löw K, Crestani F, Keist R, Benke D, Brünig I, Benson JA, Fritschy JM, Rülicke T, Bluethmann H, Möhler H, Rudolph U (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134

    Article  PubMed  Google Scholar 

  • McKernan RM, Whiting PJ (1996) Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 19:139–143

    Article  PubMed  CAS  Google Scholar 

  • McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA (A) receptor alpha1 subtype. Nat Neurosci 3:587–592

    Article  PubMed  CAS  Google Scholar 

  • Morris HV, Dawson GR, Reynolds DS, Atack JR, Stephens DN (2006) Both alpha2 and alpha3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm. Eur J Neurosci 23:2495–3504

    Article  PubMed  CAS  Google Scholar 

  • Morris HV, Nilsson S, Dixon CI, Stephens DN, Clifton PG (2009) Alpha1- and alpha2-containing GABAA receptor modulation is not necessary for benzodiazepine-induced hyperphagia. Appetite 52:675–683

    Article  PubMed  CAS  Google Scholar 

  • Platt DM, Rowlett JK, Spealman RD, Cook J, Ma C (2002) Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys. Psychopharmacology (Berl) 164:151–159

    Article  CAS  Google Scholar 

  • Platt DM, Carey GJ, Spealman RD (2005) Intravenous self-administration techniques in monkeys. In: Enna S, Williams M, Ferkany J, Kenakin T, Porsolt R, Sullivam J (eds) Current protocols in Neuroscience. Wiley, New York, Unit 9.21

    Google Scholar 

  • Pritchett DB, Lüddens H, Seeburg PH (1989) Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245:1389–1392

    Article  PubMed  CAS  Google Scholar 

  • Randall LO, Schallek W, Heise GA, Keith EF, Bagdon RE (1960) The psychosedative properties of methaminodiazepoxide. J Pharmacol Exp Ther 129:163–171

    PubMed  CAS  Google Scholar 

  • Rowlett JK, Platt DM, Lelas S, Atack JR, Dawson GR (2005) Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proc Natl Acad Sci USA 102:915–920

    Article  PubMed  CAS  Google Scholar 

  • Rowlett JK, Lelas S, Tornatzky W, Licata SC (2006) Anti-conflict effects of benzodiazepines in rhesus monkeys: relationship with therapeutic doses in humans and role of GABAA receptors. Psychopharmacology (Berl) 184:201–211

    Article  CAS  Google Scholar 

  • Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Möhler H (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid (A) receptor subtypes. Nature 401:796–800

    Article  PubMed  CAS  Google Scholar 

  • Rudolph U, Crestani F, Möhler H (2001) GABA (A) receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol Sci 22:188–194

    Article  PubMed  CAS  Google Scholar 

  • Savić MM, Clayton T, Furtmüller R, Gavrilović I, Samardzić J, Savić S, Huck S, Sieghart W, Cook JM (2008) PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA (A) receptors containing alpha5 subunits, improves passive, but not active, avoidance learning in rats. Brain Res 1208:150–159

    Article  PubMed  Google Scholar 

  • Spealman RD (1979) Comparison of drug effects on responding punished by pressurized air or electric shock delivery in squirrel monkeys: pentobarbital, chlordiazepoxide, d-amphetamine and cocaine. J Pharmacol Exp Ther 209:309–315

    PubMed  CAS  Google Scholar 

  • Stephens DN, Pistovcakova J, Worthing L, Atack JR, Dawson GR (2005) Role of GABAA alpha5-containing receptors in ethanol reward: the effects of targeted gene deletion, and a selective inverse agonist. Eur J Pharmacol 526:240–250

    Article  PubMed  CAS  Google Scholar 

  • Wafford KA, Ebert B (2008) Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time. Nat Rev Drug Discov 7:530–540

    Article  PubMed  CAS  Google Scholar 

  • Wettstein JG, Spealman RD (1986) Behavioral effects of zopiclone, CL 218,872 and diazepam in squirrel monkeys: antagonism by Ro 15-1788 and CGS 8216. J Pharmacol Exp Ther 238:522–528

    PubMed  CAS  Google Scholar 

  • Yerbury RE, Cooper SJ (1989) Novel benzodiazepine receptor ligands: palatable food intake following zolpidem, CGS 17867A, or Ro23-0364, in the rat. Pharmacol Biochem Behav 33:303–307

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the assistance of Dr. Annemarie Duggan, Kristen Bano, and Shana Langer with these studies. We also thank Dr. Roger Spealman for comments on an earlier version of this manuscript. This work was supported by USPHS grants DA11792, AA16179, and RR00168 and by a collaborative research agreement from Merck Research Laboratories with Dr. Rowlett as the principal investigator. Dr. Atack, Dr. Reynolds, and Dr. Dawson were employees of Merck Research Laboratories (Merck, Sharp & Dohme, Ltd.). Dr. Fischer and Dr. Platt had no financial relationship with Merck Research Laboratories. The agreement between Harvard Medical School and Merck Research Laboratories was a scientific collaboration and did not involve studies that by the publication thereof would engender financial gain or loss from public disclosure. None of the authors have competing personal financial interests that may be influenced by the publication of this report.

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Author notes

  1. John R. Atack

    Present address: Johnson & Johnson PR and D, Beerse, Belgium

  2. David S. Reynolds

    Present address: Discovery Biology, Pfizer Global R and D, Sandwich, Kent, UK

  3. Gerard R. Dawson

    Present address: P1Vital, University of Oxford, Warneford Hospital, Oxford, UK

Authors and Affiliations

  1. Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough, MA, 01772-9102, USA

    Bradford D. Fischer, Donna M. Platt & James K. Rowlett

  2. Neuroscience Research Centre, Merck, Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK

    John R. Atack, David S. Reynolds & Gerard R. Dawson

Authors
  1. Bradford D. Fischer
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  2. John R. Atack
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  6. James K. Rowlett
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Corresponding author

Correspondence to Bradford D. Fischer.

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Fischer, B.D., Atack, J.R., Platt, D.M. et al. Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys. Psychopharmacology 215, 311–319 (2011). https://doi.org/10.1007/s00213-010-2142-y

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  • DOI: https://doi.org/10.1007/s00213-010-2142-y

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