Patricia Di Ciano1, Patrick Mc Cormick2, Cristiana Stefan3, Ernest Wong3, Aaron Kim1, Gary Remington1,4,5,6,7, Bernard Le Foll8,9,10,11,12,13,14. 1. Translational Addiction Research Laboratory, Centre for Addiction and Mental Health (CAMH), University of Toronto, 33 Russell Street, Toronto, M5S 2S1, Canada. 2. Schizophrenia Program, CAMH, Toronto, ON, Canada. 3. Clinical Laboratory and Diagnostic Services, Centre for Addiction and Mental Health, Toronto, ON, Canada. 4. Addiction Medicine Service, Acute Care Program, CAMH, Toronto, ON, Canada. 5. CAMH, Campbell Family Mental Health Research Institute, Toronto, ON, Canada. 6. Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 7. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. 8. Translational Addiction Research Laboratory, Centre for Addiction and Mental Health (CAMH), University of Toronto, 33 Russell Street, Toronto, M5S 2S1, Canada. bernard.lefoll@camh.ca. 9. Addiction Medicine Service, Acute Care Program, CAMH, Toronto, ON, Canada. bernard.lefoll@camh.ca. 10. CAMH, Campbell Family Mental Health Research Institute, Toronto, ON, Canada. bernard.lefoll@camh.ca. 11. Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. bernard.lefoll@camh.ca. 12. Department of Pharmacology, University of Toronto, Toronto, ON, Canada. bernard.lefoll@camh.ca. 13. Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada. bernard.lefoll@camh.ca. 14. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. bernard.lefoll@camh.ca.
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.
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.
Authors: Jack Bergman; Rebecca A Roof; Cheryse A Furman; Jennie L Conroy; Nancy K Mello; David R Sibley; Phil Skolnick Journal: Int J Neuropsychopharmacol Date: 2012-07-25 Impact factor: 5.176
Authors: Bernard Le Foll; Mihail Guranda; Alan A Wilson; Sylvain Houle; Pablo M Rusjan; Victoria C Wing; Laurie Zawertailo; Usoa Busto; Peter Selby; Arthur L Brody; Tony P George; Isabelle Boileau Journal: Neuropsychopharmacology Date: 2013-08-19 Impact factor: 7.853
Authors: Patricia Di Ciano; Abhiram Pushparaj; Aaron Kim; Jessica Hatch; Talal Masood; Abby Ramzi; Maram A T M Khaled; Isabelle Boileau; Catherine A Winstanley; Bernard Le Foll Journal: PLoS One Date: 2015-09-09 Impact factor: 3.240
Authors: Bernard Le Foll; Alan A Wilson; Ariel Graff; Isabelle Boileau; Patricia Di Ciano Journal: Front Pharmacol Date: 2014-07-10 Impact factor: 5.810