title: Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release.
abstract: Pramipexole (PPX) is a high-affinity D2-like dopamine receptor agonist, used in the treatment of Parkinson's disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at a dose (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with the monoamine-depleting agent reserpine (RES), at a low dose (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release.
authors.affiliation: Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States; Dept. of Biomedical Sciences, Neuroscience Division, University of Cagliari, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Pes
authors.affiliation: Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States; Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, United States.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Godar
authors.affiliation: Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Fox
authors.affiliation: Dept. of Pharmacology, University of Washington, Seattle, WA, United States.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Burgeno
authors.affiliation: Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, United States.
authors.forename: Hunter J
authors.initials: HJ
authors.lastname: Strathman
authors.affiliation: Problem Gambling Research Studies (ProGResS) Network, University of Kansas, Lawrence, KS, United States; Dept. of Applied Behavioral Science, University of Kansas, Lawrence, KS, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Jarmolowicz
authors.affiliation: Dept. of Biomedical Sciences, Neuroscience Division, University of Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Dept. of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States.
authors.forename: Beth
authors.initials: B
authors.lastname: Levant
authors.affiliation: Dept. of Pharmacology, University of Washington, Seattle, WA, United States; Dept. of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Phillips
authors.affiliation: Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Fowler
authors.affiliation: Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States; Problem Gambling Research Studies (ProGResS) Network, University of Kansas, Lawrence, KS, United States; Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, United States. Electronic address: marco.bortolato@utah.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage*; D002421:Caudate Nucleus / Q000378:metabolism; D003657:Decision Making / Q000187:drug effects* / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010300:Parkinson Disease / Q000150:complications; D000077487:Pramipexole; D017397:Prefrontal Cortex / Q000378:metabolism; D011336:Probability; D011699:Putamen / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D012309:Risk-Taking; D012701:Serotonin / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D017448:Receptors, Dopamine D2; D012701:Serotonin; D000077487:Pramipexole; D004298:Dopamine; D009638:Norepinephrine
keywords: Dopamine; Nucleus accumbens; Pramipexole; Probability discounting; Risk taking