title: Low dose pramipexole causes D3 receptor-independent reduction of locomotion and responding for a conditioned reinforcer.
abstract: Pramipexole is a clinically important dopamine receptor agonist with reported selectivity for dopamine D3 receptors over other dopaminergic and non-dopaminergic sites. Many of its behavioural effects are therefore attributed to D3 receptor activity. Here we relate pramipexole's ex vivo D2 and D3 receptor binding (measured using [(3)H]-(+)-PHNO binding experiments) to its effects on locomotion and operant responding for primary and conditioned reinforcers. We show that pramipexole has inhibitory behavioural effects on all three behaviours at doses that occupy D3 but not D2 receptor. However, these effects are 1) not inhibited by a D3 selective dose of the antagonist SB-277011-A, and 2) present in D3 receptor knockout mice. These results suggest that a pharmacological mechanism other than D3 receptor activity must be responsible for these behavioural effects. Finally, our receptor binding results also suggest that these behavioural effects are independent of D2 receptor activity. However, firmer conclusions regarding D2 involvement would be aided by further pharmacological or receptor knock-out experiments. The implications of our findings for the understanding of pramipexole's behavioural and clinical effects are discussed.
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada. Electronic address: Patrick_mccormick@camh.net.
authors.forename: P N
authors.initials: PN
authors.lastname: McCormick
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: P J
authors.initials: PJ
authors.lastname: Fletcher
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: V S
authors.initials: VS
authors.lastname: Wilson
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: J D C
authors.initials: JD
authors.lastname: Browne
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: J N
authors.initials: JN
authors.lastname: Nobrega
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: G J
authors.initials: GJ
authors.lastname: Remington
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008124:Locomotion / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D010078:Oxazines / Q000493:pharmacokinetics; D000077487:Pramipexole; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000172:deficiency* / Q000235:genetics; D012054:Reinforcement, Psychology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D052160:Benzothiazoles; D018491:Dopamine Agonists; D009570:Nitriles; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D014316:Tritium; C042631:naxagolide; D000077487:Pramipexole
keywords: Dopamine D2 receptor; Dopamine D3 receptor; Locomotion; Operant responding; Pramipexole; [3H]-(+)-PHNO