Effects of pramipexole on impulsive choice in male wistar rats.

Abstract

Clinical reports, primarily with Parkinson's patients, note an association between the prescribed use of pramipexole (and other direct-acting dopamine agonist medications) and impulse control disorders, particularly pathological gambling. Two experiments examined the effects of acute pramipexole on rats' impulsive choices where impulsivity was defined as selecting a smallersooner over a larger-later food reward. In Experiment 1, pramipexole (0.1 to 0.3 mg/kg) significantly increased impulsive choices in a condition in which few impulsive choices were made during a stable baseline. In a control condition, in which impulsive choices predominated during baseline, pramipexole did not significantly change the same rats' choices. Experiment 2 explored a wider range of doses (0.01 to 0.3 mg/kg) using a choice procedure in which delays to the larger-later reinforcer delivery increased across trial blocks within each session. At the doses used in Experiment 1, pramipexole shifted choice toward indifference regardless of the operative delay. At lower doses of pramipexole (0.01 & 0.03 mg/kg), a trend toward more impulsive choice was observed at the 0.03 mg/kg dose. The difference in outcomes across experiments may be due to the more complex discriminations required in Experiment 2; i.e., multiple discriminations between changing delays within each session. KeywordsPramipexole; D2/D3 agonist; Impulsivity; Choice; GamblingThe Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revision DSM-IV-TR; American Psychiatric Association, 2000) classifies pathological gambling (PG) as one of several impulse control disorders. Several recent clinical reports suggest that individuals diagnosed with Parkinson's disease (PD) who are treated with dopamine (DA) agonist medications may demonstrate increased impulsivity and gambling activities which in some cases reaches pathological levels (for a review see Potenza et al., 2007). Other cases of DA agonist-related problem behavior have involved compulsive shopping and hypersexuality (Dodd et al., 2005;Driver-Dunckley et al., 2007;Giovannoni et al., 2000;Klos et al., 2005;McKeon et al., 2007;Munhoz et al., 2009;Voon et al., 2006a;Weintraub et al., 2006); two activities also classified by the DSM-IV-TR as impulse control disorders. A causal role of these DA agonist medications in the development of impulsive behaviors is suggested by the absence (or socially acceptable frequency) of impulse control disorders prior to drug therapy Corresponding Author: Gregory J. Madden, Department of Applied Behavioral Science, University of Kansas, 1000 Sunnyside Ave., Lawrence, KS 66045, gmadden@ku.edu,. Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omis...

Pramipexole‐induced Disruption of Behavioral Processes Fundamental to Intertemporal Choice

“…While acute PPX increases response latencies in both humans (Hamidovic, Kang, & de Wit, 2008) and nonhumans (Johnson, Madden, Brewer, Pinkston, & Fowler, 2011; Koffarnus et al, 2011; Madden et al, 2010), repeated administration may normalize these sedative effects (Riddle et al, 2012). We therefore examined the drug effect on mean left- and right-lever latencies in both assessments using three-way repeated-measures ANOVA (Delay Condition, Dose, Lever).…”

“…Madden, Johnson, Brewer, Pinkston, and Fowler (2010, Experiment 1), for example, administered PPX (0.1, 0.18, & 0.3 mg/kg) prior to sessions in which rats chose repeatedly between SSRs and LLRs. In their “self-control” baseline, the delay to the LLR was adjusted until SSR choice was infrequent (≤ 20%).…”

“…Sensitivity estimates from saline sessions were then compared to those from drug sessions to describe the manner in which PPX affected delay sensitivity. Within this framework, if PPX enhances sensitivity to differences in delay to reinforcement (i.e., increases preference for relative immediacy), then such an effect would manifest as increased preference for the SSR, as in Madden et al’s (2010) Experiment 1. Alternatively, if PPX diminishes delay sensitivity, then preference would shift toward the LLR (assuming sensitivity to differences in reinforcer amount remains intact).…”

Dopaminergic Influences on Emotional Decision Making in Euthymic Bipolar Patients

“…For example, the DA D2/D3 receptor agonist, pramipexole, as well as other DA receptor agonists have been implicated in the emergence of risk-seeking behaviors, such as pathological gambling in multiple case reports and cross-sectional studies in patients with Parkinson's disease (PD) (Bodi et al, 2009;Dodd et al, 2005;Lader, 2008;Pontone et al, 2006;Potenza et al, 2007;Voon et al, 2006aVoon et al, , 2006bWeintraub et al, 2006Weintraub et al, , 2010. A purported mechanism for this effect is related to pramipexole's high selective affinity for D3 receptors, which are primarily expressed in the mesocorticolimbic DA pathway-a circuitry that is active during impulsive decision making (Madden et al, 2010). Indeed, several studies that have used pramipexole in single-dose challenge paradigms have confirmed its actions on rewardrelated neural networks, primarily at low doses and in healthy individuals (Riba et al, 2008;Ye et al, 2011).…”

“…Although several studies, in both animals and humans, have demonstrated beneficial cognitive effects of pro-dopaminergic agents on measures of attention and working memory (Costa et al, 2009;Granon et al, 2000;Mattay et al, 2000;Mehta et al, 2000), there have also been reports of rare but concerning side effects, including induced impulse-control disorders in individuals with no prior history of such difficulties (Dodd et al, 2005;DriverDunckley et al, 2007;Giovannoni et al, 2000;Klos et al, 2005;Madden et al, 2010;McKeon et al, 2007;Munhoz et al, 2009;Potenza et al, 2007;Riba et al, 2008;Voon et al, 2006b;Weintraub et al, 2006). For example, the DA D2/D3 receptor agonist, pramipexole, as well as other DA receptor agonists have been implicated in the emergence of risk-seeking behaviors, such as pathological gambling in multiple case reports and cross-sectional studies in patients with Parkinson's disease (PD) (Bodi et al, 2009;Dodd et al, 2005;Lader, 2008;Pontone et al, 2006;Potenza et al, 2007;Voon et al, 2006aVoon et al, , 2006bWeintraub et al, 2006Weintraub et al, , 2010.…”