title: Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats.
abstract: Dopamine D3-preferring agonists are commonly used to treat Parkinson's disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly selective, full D3 agonist PF-592,379 to the less selective D3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naive rats failed to acquire responding when 7-OH-DPAT or PF-592,379 was made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under a FR5 or a progressive ratio (PR) schedule of reinforcement. Although 7-OH-DPAT maintained modest levels of responding when substituted under a FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D3 agonists, such as PF-592,379, will have low abuse potential in humans.
authors.affiliation: Alcohol & Drug Abuse Research Center, Division of Neuroscience, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA. gcollins@mclean.harvard.edu
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Collins
authors.forename: Paul
authors.initials: P
authors.lastname: Butler
authors.forename: Chris
authors.initials: C
authors.lastname: Wayman
authors.forename: Sian
authors.initials: S
authors.lastname: Ratcliffe
authors.forename: Paul
authors.initials: P
authors.lastname: Gupta
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Oberhofer
authors.forename: S Barak
authors.initials: SB
authors.lastname: Caine
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D012646:Self Administration; D019966:Substance-Related Disorders / Q000209:etiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D018491:Dopamine Agonists; D009025:Morpholines; C555358:PF 592379; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; D003042:Cocaine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin