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The effects of buspirone on occupancy of dopamine receptors and the rat gambling task

Abstract

Background

The dopamine D3 receptor (DRD3) has been proposed as a target for drug development for the treatment of addictive disorders. Recently, the anxiolytic buspirone has been shown to have affinity for DRD3 and DRD4, and interest in repurposing it for addictive disorders has grown.

Methods

Binding of [3H]-(+)-PHNO in the rat cerebellum and striatum was used to measure occupancy by buspirone of DRD3 or DRD2, respectively. Effects of buspirone in the rat gambling task (rGT) and the five-choice serial reaction time task (5-CSRTT) were examined.

Results

Buspirone occupied both the DRD2 and DRD3 at high doses and the DRD3, but not the DRD2, in the narrow dose range of 3 mg/kg. At 10 mg/kg, a disruption of performance on rGT was observed. All measures of performance on the rGT, except for perseverations, were affected at 3 mg/kg. On the 5-CSRTT, omissions were increased. Impairments in the rGT were not mimicked by the effects induced by satiation. Further, buspirone did not impair food-maintained responding under a progressive ratio schedule of reinforcement at any dose, suggesting that the effects of buspirone on the rGT cannot be explained by non-selective actions.

Conclusions

Although buspirone had effects on the rGT at the dose that selectively occupied the DRD3, the effects found do not parallel those found in previous studies of the effects of selective DRD3 antagonists on the rGT. Thus, buspirone may impair performance on the rGT through actions at multiple receptor sites.

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References

  • Barrus MM, Winstanley CA (2016) Dopamine D3 receptors modulate the ability of win-paired cues to increase risky choice in a rat gambling task. J Neurosci 36:785–794

    CAS  Article  PubMed  Google Scholar 

  • Bechara A, Damasio AR, Damasio H, Anderson SW (1994) Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50:7–15

    CAS  Article  PubMed  Google Scholar 

  • Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P (2013) Modification of cocaine self-administration by buspirone (buspar(R)): potential involvement of D3 and D4 dopamine receptors. Int J Neuropsychopharmacol 16:445–458

    CAS  Article  PubMed  Google Scholar 

  • Boileau I, Payer D, Chugani B, Lobo D, Behzadi A, Rusjan PM, Houle S, Wilson AA, Warsh J, Kish SJ, Zack M (2013) The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [(11) C]-(+)-propyl-hexahydro-naphtho-oxazin and [(11) C]raclopride. Addiction 108:953–963

    Article  PubMed  Google Scholar 

  • Boileau I, Payer D, Chugani B, Lobo DS, Houle S, Wilson AA, Warsh J, Kish SJ, Zack M (2014) In vivo evidence for greater amphetamine-induced dopamine release in pathological gambling: a positron emission tomography study with [(11)C]-(+)-PHNO. Mol Psychiatry 19:1305–1313

    CAS  Article  PubMed  Google Scholar 

  • Caccia S, Muglia M, Mancinelli A, Garattini S (1983) Disposition and metabolism of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in the rat. Xenobiotica 13:147–153

    CAS  Article  PubMed  Google Scholar 

  • Cocker PJ, Hosking JG, Murch WS, Clark L, Winstanley CA (2016) Activation of dopamine D receptors within the anterior cingulate cortex enhances the erroneous expectation of reward on a rat slot machine task. Neuropharmacology 105:186–195

    CAS  Article  PubMed  Google Scholar 

  • Cocker PJ, Le Foll B, Rogers RD, Winstanley CA (2013) A selective role for dopamine D receptors in modulating reward expectancy in a rodent slot machine task. Biol Psychiatry

    Google Scholar 

  • Di Ciano P, Le Foll B (2016) Evaluating the impact of naltrexone on the rat gambling task to test its predictive validity for gambling disorder. PLoS One 11:e0155604

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Ciano P, Pushparaj A, Kim A, Hatch J, Masood T, Ramzi A, Khaled MA, Boileau I, Winstanley CA, Le Foll B (2015) The impact of selective dopamine D2, D3 and D4 ligands on the rat gambling task. PLoS One 10:e0136267

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Ciano P, Underwood RJ, Hagan JJ, Everitt BJ (2003) Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-a. Neuropsychopharmacology 28:329–338

    Article  PubMed  Google Scholar 

  • Dockens RC, Salazar DE, Fulmor IE, Wehling M, Arnold ME, Croop R (2006) Pharmacokinetics of a newly identified active metabolite of buspirone after administration of buspirone over its therapeutic dose range. J Clin Pharmacol 46:1308–1312

    CAS  Article  PubMed  Google Scholar 

  • Fuller RW, Perry KW (1989) Effects of buspirone and its metabolite, 1-(2-pyrimidinyl)piperazine, on brain monoamines and their metabolites in rats. J Pharmacol Exp Ther 248:50–56

    CAS  PubMed  Google Scholar 

  • Gill KE, Beveridge TJ, Smith HR, Porrino LJ (2013) The effects of rearing environment and chronic methylphenidate administration on behavior and dopamine receptors in adolescent rats. Brain Res 1527:67–78

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Gold LH, Balster RL (1992) Effects of buspirone and gepirone on i.v. cocaine self-administration in rhesus monkeys. Psychopharmacology 108:289–294

    CAS  Article  PubMed  Google Scholar 

  • Han X, Li N, Xue X, Shao F, Wang W (2012) Early social isolation disrupts latent inhibition and increases dopamine D2 receptor expression in the medial prefrontal cortex and nucleus accumbens of adult rats. Brain Res 1447:38–43

    CAS  Article  PubMed  Google Scholar 

  • Hedlund L, Wahlstrom G (1999) Acute and long term effects of buspirone treatments on voluntary ethanol intake in a rat model of alcoholism. Alcohol Clin Exp Res 23:822–827

    CAS  Article  PubMed  Google Scholar 

  • Heidbreder CA, Gardner EL, Xi ZX, Thanos PK, Mugnaini M, Hagan JJ, Ashby CR Jr (2005) The role of central dopamine D(3) receptors in drug addiction: a review of pharmacological evidence. Brain Res Brain Res Rev 49:77–105

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Kaariainen TM, Lehtonen M, Forsberg MM, Savolainen J, Kaenmaki M, Mannisto PT (2008) Comparison of the effects of deramciclane, ritanserin and buspirone on extracellular dopamine and its metabolites in striatum and nucleus accumbens of freely moving rats. Basic Clin Pharmacol Toxicol 102:50–58

    CAS  Article  PubMed  Google Scholar 

  • Kim SW, Fowler JS, Skolnick P, Muench L, Kang Y, Shea C, Logan J, Kim D, Carter P, King P, Alexoff D, Volkow ND (2014) Therapeutic doses of buspirone block D3 receptors in the living primate brain. Int J Neuropsychopharmacol 17:1257–1267

    CAS  Article  PubMed  Google Scholar 

  • Kiss B, Horti F, Bobok A (2011) In vitro and in vivo comparison of [(3)H](+)-PHNO and [(3)H]raclopride binding to rat striatum and lobes 9 and 10 of the cerebellum: a method to distinguish dopamine D(3) from D(2) receptor sites. Synapse 65:467–478

    CAS  Article  PubMed  Google Scholar 

  • Le Foll B, Boileau I (2013) Repurposing buspirone for drug addiction treatment. Int J Neuropsychopharmacol 16:251–253

    Article  PubMed  Google Scholar 

  • Le Foll B, Frances H, Diaz J, Schwartz JC, Sokoloff P (2002) Role of the dopamine D3 receptor in reactivity to cocaine-associated cues in mice. Eur J Neurosci 15:2016–2026

    Article  PubMed  Google Scholar 

  • Le Foll B, Goldberg SR, Sokoloff P (2007) Dopamine D3 receptor ligands for the treatment of tobacco dependence. Expert Opin Investig Drugs 16:45–57

    Article  PubMed  Google Scholar 

  • Le Foll B, Guranda M, Wilson AA, Houle S, Rusjan PM, Wing VC, Zawertailo L, Busto U, Selby P, Brody AL, George TP, Boileau I (2014a) Elevation of dopamine induced by cigarette smoking: novel insights from a [(11)C]-(+)-PHNO PET study in humans. Neuropsychopharmacology 39:415–424

    Article  PubMed  Google Scholar 

  • le Foll B, Payer D, Di Ciano P, Guranda M, Nakajima S, Tong J, Mansouri E, Wilson AA, Houle S, Meyer J, Graff-Guerrero A, Boileau I (2015) Occupancy of dopamine D3 and D2 receptors by buspirone: a [11C]-(+)-PHNO PET study in humans. Neuropsychopharmacology in press

  • Le Foll B, Wilson AA, Graff A, Boileau I, Di Ciano P (2014b) Recent methods for measuring dopamine D3 receptor occupancy in vivo: importance for drug development. Front Pharmacol 5:161

    PubMed  PubMed Central  Google Scholar 

  • Linnet J, Rojskjaer S, Nygaard J, Maher BA (2006) Episodic chasing in pathological gamblers using the Iowa gambling task. Scand J Psychol 47:43–49

    Article  PubMed  Google Scholar 

  • Liu YP, Wilkinson LS, Robbins TW (2004) Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex. Psychopharmacology 173:175–185

    CAS  Article  PubMed  Google Scholar 

  • Malone DT, Kearn CS, Chongue L, Mackie K, Taylor DA (2008) Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats. Neuroscience 152:265–272

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Martres MP, Sales N, Bouthenet ML, Schwartz JC (1985) Localisation and pharmacological characterisation of D-2 dopamine receptors in rat cerebral neocortex and cerebellum using [125I]iodosulpride. Eur J Pharmacol 118:211–219

    CAS  Article  PubMed  Google Scholar 

  • McCormick PN, Fletcher PJ, Wilson VS, Browne JD, Nobrega JN, Remington GJ (2015) Low dose pramipexole causes D3 receptor-independent reduction of locomotion and responding for a conditioned reinforcer. Neuropharmacology 89:225–231

    CAS  Article  PubMed  Google Scholar 

  • McCormick PN, Kapur S, Graff-Guerrero A, Raymond R, Nobrega JN, Wilson AA (2010) The antipsychotics olanzapine, risperidone, clozapine, and haloperidol are D2-selective ex vivo but not in vitro. Neuropsychopharmacology 35:1826–1835

    CAS  PubMed  PubMed Central  Google Scholar 

  • McCormick PN, Wilson VS, Wilson AA, Remington GJ (2013) Acutely administered antipsychotic drugs are highly selective for dopamine D2 over D3 receptors. Pharmacol Res: Off J Italian Pharmacol Soc 70:66–71

    CAS  Article  Google Scholar 

  • Mello NK, Fivel PA, Kohut SJ (2013a) Effects of chronic buspirone treatment on nicotine and concurrent nicotine+cocaine self-administration. Neuropsychopharmacology 38:1264–1275

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Mello NK, Fivel PA, Kohut SJ, Bergman J (2013b) Effects of chronic buspirone treatment on cocaine self-administration. Neuropsychopharmacology 38:455–467

    CAS  Article  PubMed  Google Scholar 

  • Nader MA, Barrett JE (1990) Effects of chlordiazepoxide, buspirone and serotonin receptor agonists and antagonists on responses of squirrel monkeys maintained under second-order schedules of intramuscular cocaine injection or food presentation. Drug Dev Res 20:5–17

    CAS  Article  Google Scholar 

  • Narendran R, Slifstein M, Guillin O, Hwang Y, Hwang DR, Scher E, Reeder S, Rabiner E, Laruelle M (2006) Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo. Synapse 60:485–495

    CAS  Article  PubMed  Google Scholar 

  • Newman AH, Blaylock BL, Nader MA, Bergman J, Sibley DR, Skolnick P (2012) Medication discovery for addiction: translating the dopamine D3 receptor hypothesis. Biochem Pharmacol 84:882–890

    CAS  Article  PubMed  Google Scholar 

  • Petry NM (2001) Substance abuse, pathological gambling, and impulsiveness. Drug Alcohol Depend 63:29–38

    CAS  Article  PubMed  Google Scholar 

  • Rilke O, Jahkel M, Oehler J (1998) Dopaminergic parameters during social isolation in low- and high-active mice. Pharmacol Biochem Behav 60:499–505

    CAS  Article  PubMed  Google Scholar 

  • Rilke O, May T, Oehler J, Wolffgramm J (1995) Influences of housing conditions and ethanol intake on binding characteristics of D2, 5-HT1A, and benzodiazepine receptors of rats. Pharmacol Biochem Behav 52:23–28

    CAS  Article  PubMed  Google Scholar 

  • Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380

    CAS  Article  PubMed  Google Scholar 

  • Roberts DCS, Richardson NR (1992) Self-administration of psychomotor stimulants using progressive ratio schedules of reinforcement. In: Boulton A, Baker G, Wu PH (eds), Neuromethods, Vol. 24: animal models of drug addiction. The Humana Press, Inc.

  • Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine beta-hydroxylase. Neuropsychopharmacology 35:2440–2449

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Seedat S, Kesler S, Niehaus DJ, Stein DJ (2000) Pathological gambling behaviour: emergence secondary to treatment of Parkinson’s disease with dopaminergic agents. Depression Anxiety 11:185–186

    CAS  Article  PubMed  Google Scholar 

  • Simpson J, Kelly JP (2012) The effects of isolated and enriched housing conditions on baseline and drug-induced behavioural responses in the male rat. Behav Brain Res 234:175–183

    Article  PubMed  Google Scholar 

  • Tunnicliff G (1991) Molecular basis of buspirone’s anxiolytic action. Pharmacol Toxicol 69:149–156

    CAS  Article  PubMed  Google Scholar 

  • Wilson AA, McCormick P, Kapur S, Willeit M, Garcia A, Hussey D, Houle S, Seeman P, Ginovart N (2005) Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography. J Med Chem 48:4153–4160

    CAS  Article  PubMed  Google Scholar 

  • Zeeb FD, Robbins TW, Winstanley CA (2009) Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task. Neuropsychopharmacology 34:2329–2343

    CAS  Article  PubMed  Google Scholar 

  • Zeeb FD, Wong AC, Winstanley CA (2013) Differential effects of environmental enrichment, social-housing, and isolation-rearing on a rat gambling task: dissociations between impulsive action and risky decision-making. Psychopharmacology 225:381–395

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

Dr. Remington has received consultant fees from Neurocrine Biosciences, Novartis, and Synchroneuron, as well as grant support from Novartis. Dr. Le Foll has received speaker fees or consulting fees from Mettrum and CCIC. He also received salary/grant support from Pfizer and Bioprojet and in kind support from GW Pharma, Mylan pharmaceutical, and Brainsway

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Correspondence to Bernard Le Foll.

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Di Ciano, P., Cormick, P.M., Stefan, C. et al. The effects of buspirone on occupancy of dopamine receptors and the rat gambling task. Psychopharmacology 234, 3309–3320 (2017). https://doi.org/10.1007/s00213-017-4715-5

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  • DOI: https://doi.org/10.1007/s00213-017-4715-5

Keywords

  • Dopamine
  • Serotonin
  • Occupancy
  • PHNO