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1.  Effects of Acute Pramipexole on Preference for Gambling-like Schedules of Reinforcement in Rats 
Psychopharmacology  2010;213(1):11-18.
Pramipexole and other direct dopamine agonist medications have been implicated in the development of impulsive behavior such as pathological gambling among those taking the drug to control symptoms of Parkinson’s disease or restless leg syndrome. Few laboratory studies examining pramipexole’s effects on gambling-like behavior have been conducted.
The present study used a rodent model approximating some aspects of human gambling to examine within-subject effects of acute pramipexole (0.03, 0.1, 0.18, & 0.3 mg/kg) on rat’s choices to earn food reinforcement by completing variable-ratio (i.e., gambling-like) or fixed-ratio response requirements.
In a condition in which the variable-ratio alternative was rarely selected, all but the lowest dose of pramipexole significantly increased choice of the variable-ratio alternative (an average of 15% above saline).. The same doses did not affect choice significantly in a control condition designed to evaluate the involvement of nonspecific drug effects. Pramipexole increased latencies to initiate trials (+ 9.12 s) and to begin response runs on forced-choice trials (variable-ratio: + 0.21 s; fixed-ratio: + 0.88 s), but did not affect measures of response perseveration (conditional probabilities of “staying”).
The findings are consistent with clinical reports linking pramipexole to the expression of increased gambling in humans. Results are discussed in the context of neurobehavioral evidence suggesting that dopamine agonists increase sensitivity to reward delay and disrupt appropriate feedback from negative outcomes.
PMCID: PMC3747984  PMID: 20814781
pramipexole; dopamine agonist; gambling; impulsive behavior; Parkinson’s disease; rat
2.  Dopaminergic Influences on Emotional Decision Making in Euthymic Bipolar Patients 
Neuropsychopharmacology  2013;39(2):274-282.
We recently reported that the D2/D3 agonist pramipexole may have pro-cognitive effects in euthymic patients with bipolar disorder (BPD); however, the emergence of impulse-control disorders has been documented in Parkinson's disease (PD) after pramipexole treatment. Performance on reward-based tasks is altered in healthy subjects after a single dose of pramipexole, but its potential to induce abnormalities in BPD patients is unknown. We assessed reward-dependent decision making in euthymic BPD patients pre- and post 8 weeks of treatment with pramipexole or placebo by using the Iowa Gambling Task (IGT). The IGT requires subjects to choose among four card decks (two risky and two conservative) and is designed to promote learning to make advantageous (conservative) choices over time. Thirty-four BPD patients completed both assessments (18 placebo and 16 pramipexole). Baseline performance did not differ by treatment group (F=0.63; p=0.64); however, at week 8, BPD patients on pramipexole demonstrated a significantly greater tendency to make increasingly high-risk, high-reward choices across the five blocks, whereas the placebo group's pattern was similar to that reported in healthy individuals (treatment × time × block interaction, p<0.05). Analyses of choice strategy using the expectancy valence model revealed that after 8 weeks on pramipexole, BPD patients attended more readily to feedback related to gains than to losses, which could explain the impaired learning. There were no significant changes in mood symptoms over the 8 weeks, and no increased propensity toward manic-like behaviors were reported. Our results suggest that the enhancement of dopaminergic activity influences risk-associated decision-making performance in euthymic BPD. The clinical implications remain unknown.
PMCID: PMC3870768  PMID: 23884342
Behavioral Science; bipolar disorder; decision-making; Dopamine; gambling; Mood/Anxiety/Stress Disorders; Neuropharmacology; pramipexole; bipolar disorder; dopamine; pramipexole; decision-making
3.  Delay Discounting and Gambling 
Behavioural processes  2011;87(1):43-49.
Delay discounting describes the decline in the value of a reinforcer as the delay to that reinforcer increases. A review of the available studies revealed that steep delay discounting is positively correlated with problem or pathological gambling. One hypothesis regarding this correlation derives from the discounting equation proposed by Mazur (1989). According to the equation, steeper discounting renders the difference between fixed-delayed rewards and gambling-like variable-delayed rewards larger; with the latter being more valuable. The present study was designed to test this prediction by first assessing rats’ impulsive choices across four delays to a larger-later reinforcer. A second condition quantified strength of preference for mixed- over fixed-delays, with the duration of the latter adjusted between sessions to achieve indifference. Strength of preference for the mixed-delay alternative is given by the fixed delay at indifference (lower fixed-delay values reflect stronger preferences). Percent impulsive choice was not correlated with the value of the fixed delay at indifference and, therefore, the prediction of the hyperbolic model of gambling was not supported. A follow-up assessment revealed a significant decrease in impulsive choice after the second condition. This shift in impulsive choice could underlie the failure to observe the predicted correlation between impulsive choice and degree of preference for mixed- over fixed delays.
PMCID: PMC3081402  PMID: 21352902
Delay discounting; impulsivity; delay; gambling; rat
4.  Environmental Rearing Effects on Impulsivity and Reward Sensitivity 
Behavioral neuroscience  2013;127(5):712-724.
Previous research has indicated that rearing in an enriched environment may promote self-control in an impulsive choice task. To further assess the effects of rearing environment on impulsivity, 2 experiments examined locomotor activity, impulsive action, impulsive choice, and different aspects of reward sensitivity and discrimination. In Experiment 1, rats reared in isolated or enriched conditions were tested on an impulsive choice procedure with a smaller-sooner versus a larger-later reward, revealing that the isolated rats valued the smaller-sooner reward more than the enriched rats. A subsequent reward challenge was presented in which the delay to the 2 rewards was the same but the magnitude difference remained. The enriched rats did not choose the larger reward as often as the isolated rats, reflecting poorer reward discrimination. Impulsive action was assessed using a differential-reinforcement-of-low-rate task, which revealed deficits in the enriched rats. In Experiment 2, rats reared in isolated, standard, or enriched conditions were tested on reward contrast and reward magnitude sensitivity procedures. The rats were presented with 2 levers that delivered different magnitudes of food on variable interval 30-s schedules. Across all tests, the enriched and social rats displayed more generalized responding to the small-reward lever, but a similar response to the large-reward lever, compared with the isolated rats. This confirmed the results of Experiment 1, indicating poorer reward discrimination in the enriched condition compared with the isolated condition. The results suggest that enrichment may moderate reward generalization/discrimination processes through alterations in incentive motivational processes.
PMCID: PMC3906647  PMID: 24128360
environmental enrichment; isolation rearing; impulsive choice; impulsive action; reward processing
5.  Effects of Acute Pramipexole on Male Rats’ Preference for Gambling-like Rewards II 
Pramipexole (PPX) is a dopamine agonist medication that has been implicated in the development of pathological gambling and other impulse control disorders. Johnson, Madden, Brewer, Pinkston, and Fowler (2011) reported that PPX increased male rats’ preference for gambling-like rewards (those arranged according to a variable-ratio schedule) over predictable rewards (those obtained from a fixed-ratio schedule). The present experiment explored the possibility that Johnson et al. underestimated the effects of PPX on gambling-like choices by constraining their rats’ daily income. In the present experiment conducted in a closed economy, PPX produced a dose-related increase in choice of the gambling-like alternative. In a control condition, PPX did not disrupt choice, suggesting the increased preference for gambling-like rewards was not due to nonspecific drug effects. Our findings are qualitatively consistent with those of Johnson et al., although the dose-related effect and larger effect size in the current study suggest that the effect of PPX on gambling-like choices is more pronounced when income was not constrained. This finding is consistent with clinical reports suggesting PPX is related to the development of problem gambling in humans.
PMCID: PMC3482126  PMID: 22288460
pramipexole; dopamine agonist; gambling; Parkinson’s disease; rat
6.  Extended access to amphetamine self-administration increases impulsive choice in a delay discounting task in rats 
Psychopharmacology  2009;207(3):391-400.
d-Amphetamine (AMPH) is a widely prescribed ADHD medication, but little is known about its effects on impulsive choice with escalated use.
The current study examined the effects of short and long access to AMPH self-administration on impulsive choice in a delay discounting task in which rats chose between a small immediate reward (1 sucrose pellet immediately) and a larger delayed reward (3 sucrose pellets after an adjusting delay).
Following choice stability in delay discounting, all rats received 15 1-hour sessions of AMPH self-administration (0.1 or 0.03 mg/kg/infusion); self-administration sessions began 45 min after each delay discounting session. Rats were then either maintained on the short access (ShA) self-administration session or were switched to a long access (LgA) 6-hour session for 21 days, followed by a 7-day withdrawal phase in which only the delay discounting task continued.
LgA rats in the 0.03 mg/kg/infusion dose group escalated in total number of infusions across sessions, although rats in the 0.1 mg/kg/infusion dose group did not. LgA groups at both unit doses showed decreased mean adjusted delays across sessions compared to the ShA groups, indicating that long access to AMPH increases impulsive choice. During the AMPH withdrawal phase, LgA groups returned back to baseline mean adjusted delays, indicating that the effect on impulsive choice was reversible.
These results show that extended AMPH self-administration produces a transient loss of inhibitory control, which may play a role in the escalating pattern of drug intake that characterizes the addiction process.
PMCID: PMC3164508  PMID: 19784636
Delay Discounting; d-Amphetamine; Escalation; Impulsivity
7.  Impulsive choice and environmental enrichment: Effects of d-amphetamine and methylphenidate 
Behavioural brain research  2008;193(1):48-54.
Individual differences in impulsive choice and rearing in differential environments are factors that predict vulnerability to drug abuse. The present study determined if rearing influences impulsive choice, and if d-amphetamine or methylphenidate alters impulsive choice in differentially-reared rats. Male Sprague-Dawley rats were raised from 21 days of age in either an enriched condition (EC) or an isolated condition (IC) and were tested as young adults on an adjusting delay task. In this task, two levers were available and a response on one lever yielded one 45 mg food pellet immediately, whereas a response on the other yielded three pellets after an adjusting delay. The delay was initially set at 6 sec, and it decreased or increased by 1 sec following responses on the immediate or delayed levers, respectively. A mean adjusted delay (MAD) was calculated upon completion of each daily session, and it served as the quantitative measure of impulsivity. Once MADs stabilized, rats were injected with saline, d-amphetamine (0.5, 1.0, or 2.0 mg/kg, s.c.), or methylphenidate (2.5, 5.0, or 10.0 mg/kg, s.c.) 15 min prior to adjusting delay sessions. EC rats had higher baseline MADs (were less impulsive) than IC rats. Additionally, administration of d-amphetamine, but not methylphenidate, dose-dependently increased impulsive choice (decreased MADs) in EC rats. In IC rats, d-amphetamine and methylphenidate dose-dependently decreased impulsivity (increased MADs). These results indicate that rearing environment influences impulsive choice and moderates the effect of psychostimulants on impulsive choice. Specifically, psychostimulants may decrease environment-dependent impulsive choice in individuals with high levels of impulsivity (e.g., those with ADHD), whereas they may increase impulsive choice in individuals with low levels of impulsivity.
PMCID: PMC2681296  PMID: 18534693
amphetamine; delay discounting; environmental enrichment; individual differences; impulsive choice; methylphenidate
8.  Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research 
Translational Psychiatry  2013;3(8):e297-.
Mood disorders, such as major depressive disorder, are characterized by abnormal reward responsiveness. The Response Bias Probabilistic Reward Task (hereafter referred to as probabilistic reward task (PRT)) quantifies reward responsiveness in human subjects, and an equivalent animal assessment is needed to facilitate preclinical translational research. Thus, the goals of the present studies were to develop, validate and characterize a rat analog of the PRT. Adult male Wistar and Long–Evans rats were trained in operant testing chambers to discriminate between two tone stimuli that varied in duration (0.5 and 2 s). During a subsequent test session consisting of 100 trials, the two tones were made ambiguous (0.9 and 1.6 s) and correct identification of one tone was reinforced with a food pellet three times more frequently than the other tone. In subsequent experiments, Wistar rats were administered either a low dose of the dopamine D2/D3 receptor agonist pramipexole (0.1 mg kg−1, subcutaneous) or the psychostimulant amphetamine (0.5 mg kg−1, intraperitoneal) before the test session. Similar to human subjects, both rat strains developed a response bias toward the more frequently reinforced stimulus, reflecting robust reward responsiveness. Mirroring prior findings in humans, a low dose of pramipexole blunted response bias. Moreover, in rats, amphetamine potentiated response bias. These results indicate that in rats, reward responsiveness can be quantified and bidirectionally modulated by pharmacological manipulations that alter striatal dopamine transmission. Thus, this new procedure in rats, which is conceptually and procedurally analogous to the one used in humans, provides a reverse translational platform to investigate abnormal reward responsiveness across species.
PMCID: PMC3756297  PMID: 23982629
anhedonia; animal model; depression; dopamine; rat; reward
9.  Building blocks of self-control: increased tolerance for delay with bundled rewards. 
Impulsive choice can be defined as temporary preference for a smaller-sooner reward (SS) over a larger-later reward (LL). Hyperbolic discounting implies that impulsive choices will occur less when organisms choose between a series of SSs versus LLs all at once than when they choose between single SS versus LL pairs. Eight rats were exposed to two conditions of an intertemporal choice paradigm using sucrose solution as reward. In both conditions, the LL was 150 microl delayed by 3 s, while the SS was an immediate reward that ranged from 25-150 microl across sessions. Preference for the LL was greater when the chosen reward was automatically delivered three times in succession (bundled) than when it was chosen singly and delivered after each choice. For each of the 8 rats, the estimated SS amount that produced indifference was higher in the bundled condition than in the single condition. Because bundling in humans may be based on the perception that one's current choice is predictive of future choices, the data presented here may demonstrate an important building block of self-control.
PMCID: PMC1284920  PMID: 12696740
10.  Single Dose of a Dopamine Agonist Impairs Reinforcement Learning in Humans: Behavioral Evidence from a Laboratory-based Measure of Reward Responsiveness 
Psychopharmacology  2007;196(2):221-232.
The dopaminergic system, particularly D2-like dopamine receptors, has been strongly implicated in reward processing. Animal studies have emphasized the role of phasic dopamine (DA) signaling in reward-related learning, but these processes remain largely unexplored in humans.
To evaluate the effect of a single, low dose of a D2/D3 agonist—pramipexole—on reinforcement learning in healthy adults. Based on prior evidence indicating that low doses of DA agonists decrease phasic DA release through autoreceptor stimulation, we hypothesized that 0.5 mg of pramipexole would impair reward learning due to presynaptic mechanisms.
Using a double-blind design, a single 0.5 mg dose of pramipexole or placebo was administered to 32 healthy volunteers, who performed a probabilistic reward task involving a differential reinforcement schedule as well as various control tasks.
As hypothesized, response bias toward the more frequently rewarded stimulus was impaired in the pramipexole group, even after adjusting for transient adverse effects. In addition, the pramipexole group showed reaction time and motor speed slowing and increased negative affect; however, when adverse physical side effects were considered, group differences in motor speed and negative affect disappeared.
These findings show that a single low dose of pramipexole impaired the acquisition of reward-related behavior in healthy participants, and they are consistent with prior evidence suggesting that phasic DA signaling is required to reinforce actions leading to reward. The potential implications of the present findings to psychiatric conditions, including depression and impulse control disorders related to addiction, are discussed.
PMCID: PMC2268635  PMID: 17909750
Dopamine; D2 agonists; Reward Processing; Depression; Mesolimbic System; Addiction
11.  Effects of Selective Dopaminergic Compounds on a Delay Discounting Task 
Behavioural pharmacology  2011;22(4):300-311.
Impulsivity is widely regarded as a multidimensional trait that encompasses two or more distinct patterns of behavior, and dopaminergic systems are implicated in the expression of impulsive behavior in both humans and animals. Impulsive choice, or the tendency to choose rewards associated with relatively little or no delay, has been extensively studied in humans and animals using delay discounting tasks. Here, delay discounting procedures were used to assess the effects of receptor-selective dopaminergic agonists, antagonists, and dopamine transporter ligands on choices of immediate versus delayed sucrose pellets. The effects of d-amphetamine, GBR 12909, apomorphine, SKF 81297, sumanirole, pramipexole, ABT-724, SCH 23390, L-741,626, PG01037, and L-745,870 were assessed in 24 Sprague Dawley rats. The only drugs to affect impulsive choice selectively without altering undelayed choice were the D1-like antagonist SCH 23390 (0.01 mg/kg) and the D4 partial agonist ABT-724 (3.2 mg/kg), which both increased impulsive choice. The shared effects of these compounds may be explained by their localization within the prefrontal cortex on different groups of neurons. None of the selective agonists and antagonists tested reduced impulsive choice, so further research is needed to determine if direct dopaminergic agonists or antagonists may be therapeutically useful in the treatment of impulse-control disorders.
PMCID: PMC3135665  PMID: 21694584
Delay discounting; inter-temporal choice; impulsive choice; impulsivity; self control; dopamine; SCH 23390; ABT-724; rat
12.  Effects of acute and repeated nicotine administration on delay discounting in Lewis and Fischer 344 rats 
Behavioural pharmacology  2010;21(8):754-764.
Biological differences may underlie individual differences in impulsive behavior, such as choice for a smaller, more immediate reinforcer over a larger, more delayed reinforcer. Repeated exposure to drugs of abuse may have differing effects on such behavior. To evaluate acute and repeated effects of nicotine on impulsive choice, two strains of rats that have been shown to differ in impulsive choice were tested in a delay-discounting paradigm. Eight Lewis and eight Fischer 344 rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after a delay. The delay systematically increased in blocks of trials within each session, and the delay value at which choice for the two alternatives was equal (i.e., the indifference point) was interpolated. Effects of nicotine (0.1 – 1.0 mg/kg, s.c.) on percent choice and indifference points were determined during the acute-testing phase and during the re-determination of effects of each dose following at least 30 sessions of repeated 1.0 mg/kg nicotine exposure. Lewis rats had shorter indifference points (i.e., made fewer larger reinforcer choices) than the Fischer 344 rats. Acute nicotine administration increased mean larger-reinforcer choices at the 0.3 mg/kg dose in the Lewis rats and at the 1.0 mg/kg dose in the Fischer 344 rats. After repeated exposure to nicotine, indifference points returned to near baseline (pre-drug) levels for both strains. Strain differences were observed in rates of delay discounting and nicotine may decrease impulsive choice acutely, but this effect does not appear to be long-lasting.
PMCID: PMC3046322  PMID: 20944502
choice; delay discounting; Fischer 344; impulsivity; Lewis; nicotine; rat; self-control; temporal discounting
Psychopharmacology  2011;219(1):123-135.
Dopamine D2-like agonists maintain responding when substituted for cocaine in laboratory animals. However, these effects appear to be mediated by an interaction with stimuli that were previously paired with cocaine reinforcement (CS).
To evaluate the extent to which the pramipexole-maintained and -induced responding are influenced by cocaine-paired stimuli.
Rats were trained to nosepoke for cocaine under fixed ratio 1 (FR1) or progressive ratio (PR) schedules of reinforcement. In FR1-trained rats, pramipexole was substituted for cocaine with injections either paired with CSs, or delivered in their absence. The capacity of experimenter-administered pramipexole to induce FR1 and PR responding for CS presentation was evaluated. The effects of altering stimulus conditions, as well as pretreatments with D2- (L-741,626) and D3-preferring (PG01037) antagonists on pramipexole-induced PR responding were also evaluated.
When substituted for cocaine, pramipexole maintained responding at high rates when injections were paired with CSs, but low rates when CSs were omitted. Similarly, experimenter-administered pramipexole induced dose-dependent increases in FR1 or PR responding, with high rates of responding observed when the CS was presented, and low rates of responding when CS presentation was omitted. D2 and D3 antagonists differentially affected pramipexole-induced PR responding, with L-741,626 and PG01037 producing rightward, and downward shifts in the dose-response curve for CS-maintained responding, respectively.
These data indicate that pramipexole is capable of enhancing the reinforcing effectiveness of conditioned stimuli, and raise the possibility that similar mechanisms are responsible for the increased occurrence of impulse control disorders in patients being treated with pramipexole.
PMCID: PMC3800033  PMID: 21701814
14.  Strain Differences in Delay Discounting between Lewis and Fischer 344 Rats at Baseline and Following Acute and Chronic Administration of d-Amphetamine 
Stimulant drugs have been shown either to increase or decrease rates of delay discounting (impulsive choice). These mixed findings may result from genetic, neurochemical, or environmental factors. Lewis (LEW) and Fischer 344 (F344) rats have neurochemical and behavioral differences that may be relevant to delay discounting and were used to examine effects of acute and chronic administration of d-amphetamine (d-AMP) on impulsive choice using a within-session delay-discounting procedure. Male LEW (n=8) and F344 (n=8) rats chose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. Saline and d-AMP (0.1, 0.3, 1.0, and 1.7 mg/kg) were tested acutely and during chronic d-AMP exposure. Choice for the larger reinforcer decreased as the delay to its presentation increased for both strains at baseline. LEW rats made more impulsive choices than F344 rats as indicated by shorter indifference points, and this is consistent with previous research. Acute administration of d-AMP dose dependently increased larger-reinforcer choice and area under the curve (AUC) for LEW, but not F344 rats. During chronic exposure to d-AMP, larger-reinforcer choice and AUC increased relative to acute administration for F344 rats responding in shorter delay series, but not for F344 rats responding in longer delay series or for LEW rats. Differential effects of acute and chronic administration of d-AMP on impulsive choice in LEW and F344 rats may be a result of various factors, including genetic, neurochemical, and environmental variables. Future research should attempt to tease apart the relative contribution of each of these factors on impulsive choice.
PMCID: PMC3310270  PMID: 22342664
d-Amphetamine; Delay discounting; Fischer 344; Impulsivity; Lewis; Rat; Self-control
15.  Pramipexole-Induced Disruption of Behavioral Processes Fundamental to Intertemporal Choice 
Evaluating the effects of presession drug administration on intertemporal choice in nonhumans is a useful approach for identifying compounds that promote impulsive behavior in clinical populations, such as those prescribed the dopamine agonist pramipexole (PPX). Based on the results of previous studies, it is unclear whether PPX increases rats’ impulsive choice or attenuates aspects of stimulus control. The present study was designed to experimentally isolate behavioral processes fundamental to intertemporal choice and challenge them pharmacologically with PPX administration. In Experiment 1, the hypothesis that PPX increases impulsive choice as a result of enhanced sensitivity to reinforcer delays was tested and disconfirmed. That is, acute PPX diminished delay sensitivity in a manner consistent with disruption of stimulus control whereas repeated PPX had no effect on delay sensitivity. Experiments 2 and 3 elaborated upon this finding by examining the effects of repeated PPX on rats’ discrimination of response–reinforcer contingencies and reinforcer amounts, respectively. Accuracy of both discriminations was reduced by PPX. Collectively these results provide no support for past studies that have suggested PPX increases impulsive choice. Instead, PPX impairs stimulus control over choice behavior. The behavioral approach adopted herein could be profitably integrated with genetic and other biobehavioral models to advance our understanding of impulsive behavior associated with drug administration.
PMCID: PMC4161207  PMID: 23436721
impulsive choice; pramipexole; stimulus control; lever press; rat
16.  Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial 
Lancet Neurology  2013;12(8):747-755.
In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD).
Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30–79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with, number NCT00321854.
Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (−0·4 points, 95% CI −2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was −15·1% (SE 2·1) for early and −14·6% (2·0) for delayed pramipexole (difference −0·5 percentage points, 95% CI −5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug.
By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6–9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects.
Boehringer Ingelheim GmbH.
PMCID: PMC3714436  PMID: 23726851
17.  Dopamine Agonists Diminish Value Sensitivity of the Orbitofrontal Cortex: A Trigger for Pathological Gambling in Parkinson’s Disease? 
The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson’s disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.
PMCID: PMC2972251  PMID: 19741594 CAMSID: cams1534
fMRI; impulse control disorder; dopamine agonist; reward; addiction; reinforcement
Many drugs of abuse produce changes in impulsive choice, that is, choice for a smaller–sooner reinforcer over a larger–later reinforcer. Because the alternatives differ in both delay and amount, it is not clear whether these drug effects are due to the differences in reinforcer delay or amount. To isolate the effects of delay, we used a titrating delay procedure. In phase 1, 9 rats made discrete choices between variable delays (1 or 19 s, equal probability of each) and a delay to a single food pellet. The computer titrated the delay to a single food pellet until the rats were indifferent between the two options. This indifference delay was used as the starting value for the titrating delay for all future sessions. We next evaluated the acute effects of nicotine (subcutaneous 1.0, 0.3, 0.1, and 0.03 mg/kg) on choice. If nicotine increases delay discounting, it should have increased preference for the variable delay. Instead, nicotine had very little effect on choice. In a second phase, the titrated delay alternative produced three food pellets instead of one, which was again produced by the variable delay (1 s or 19 s) alternative. Under this procedure, nicotine increased preference for the one pellet alternative. Nicotine-induced changes in impulsive choice are therefore likely due to differences in reinforcer amount rather than differences in reinforcer delay. In addition, it may be necessary to include an amount sensitivity parameter in any mathematical model of choice when the alternatives differ in reinforcer amount.
PMCID: PMC2648523  PMID: 19794835
risk; impulsive choice; reinforer delay; reinforcer amount; nicotine; lever press; rats
Previous research has shown that Lewis rats make more impulsive choices than Fischer 344 rats. Such strain-related differences in choice are important as they may provide an avenue for exploring genetic and neurochemical contributions to impulsive choice. The present systematic replication was designed to determine if these findings could be reproduced using a procedure less susceptible to within- or between-session carry-over effects that may have affected previous findings. Specifically, delays to the larger–later food reinforcer were manipulated between conditions following steady-state assessments of choice, and the order of delays across conditions was mixed. The results confirmed previous findings that Lewis rats made significantly more impulsive choices than Fischer 344 rats. Fischer 344 rats' preference for the larger–later reinforcer, on the other hand, was less extreme than reported in prior research, which may be due to carry-over effects inherent to the commonly used technique of systematically increasing delays within session. Previously reported across-strain motor differences were reproduced as Lewis rats had shorter latencies than Fischer 344 rats, although these latencies were not correlated with impulsive choice. Parallels between reduced dopamine function in Lewis rats and clinical reports of impulse-control disorders following treatment of Parkinson patients with selective D2/D3 dopamine agonists are discussed.
PMCID: PMC2582207  PMID: 19070340
Fischer 344 rats; Lewis rats; choice; impulsivity; delay-discounting; rat; lever press
20.  The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats 
Psychopharmacology  2012;226(1):127-138.
Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice.
Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice.
Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755.
Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition.
NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low-impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used.
PMCID: PMC3572289  PMID: 23104264
Impulsivity; Delay discounting; Ketamine; Memantine; D-AP-5 or AP-5 or D-AP5 or AP5; CGS 19755; Glutamate; NMDA receptor antagonist; Decision making; Impulsive choice
21.  The discriminative stimulus effects of dopamine D2- and D3-preferring agonists in rats 
Psychopharmacology  2008;203(2):317-327.
Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors.
The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists.
Materials and methods
Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole.
Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group.
Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role.
PMCID: PMC3065021  PMID: 18807248
Drug discrimination; Either/or discrimination; D2; D3; Dopamine; Pramipexole; Sumanirole; Rat
22.  Chronic pramipexole treatment increases tolerance for sucrose in normal and ventral tegmental lesioned rats 
The loss of dopamine neurons observed in Parkinson's disease (PD) elicits severe motor control deficits which are reduced by the use of dopamine agonists. However, recent works have indicated that D3-preferential agonists such as pramipexole can induce impulse control disorders (ICDs) such as food craving or compulsive eating. In the present study, we performed an intermittent daily feeding experiment to assess the effect of chronic treatment by pramipexole and VTA bilateral lesion on tolerance for sucrose solution. The impact of such chronic treatment on spontaneous locomotion and spatial memory was also examined. Changes in sucrose tolerance could indicate the potential development of a change in food compulsion or addiction related to the action of pramipexole. Neither the bilateral lesion of the VTA nor chronic treatment with pramipexole altered the spontaneous locomotion or spatial memory in rats. Rats without pramipexole treatment quickly developed a stable intake of sucrose solution in the 12 h access phase. On the contrary, when under daily pramipexole treatment, rats developed a stronger and ongoing escalation of their sucrose solution intakes. In addition, we noted that the change in sucrose consumption was sustained by an increase of the expression of the Dopamine D3 receptor in the core and the shell regions of the nucleus accumbens. The present results may suggest that long-term stimulation of the Dopamine D3 receptor in animals induces a strong increase in sucrose consumption, indicating an effect of this receptor on certain pathological aspects of food eating.
PMCID: PMC4285017  PMID: 25610366
sucrose tolerance; ventral tegmenta area; Parkinson's disease; dopamine agonist; pramipexole; food compulsion
23.  Unidirectional relationship between heroin self-administration and impulsive decision-making in rats 
Psychopharmacology  2011;219(2):443-452.
There is growing clinical evidence for a strong relationship between drug addiction and impulsivity. However, it is not fully clear whether impulsivity is a pre-existing trait or a consequence of drug abuse. Recent observations in the animal models show that pre-existing levels of impulsivity predict cocaine and nicotine seeking. Whether such relationships also exist with respect to non-stimulant drugs is largely unknown.
We studied the relationship between impulsive choice and vulnerability to heroin taking and seeking.
Materials and methods
Rats were selected in the delayed reward task based on individual differences in impulsive choice. Subsequently, heroin intravenous self-administration behaviour was analysed, including acquisition of heroin intake, motivation, extinction and drug- and cue-induced reinstatement. Throughout the entire experiment, changes in impulsive choice were monitored weekly.
Results and discussion
High impulsivity did not predict measures of heroin taking. Moreover, high impulsive rats did not differ from low impulsive rats in extinction rates or heroin- and cue-induced reinstatement. However, both groups became more impulsive as heroin self-administration continued. During abstinence, impulsivity levels returned towards baseline (pre-heroin) levels. Our results indicate that, in contrast to psychostimulants, impulsive choice does not predict vulnerability to heroin seeking and taking.
These data implicate that different neural mechanisms may underlie the vulnerability to opiate and psychostimulant dependence. Moreover, our data suggest that elevated impulsivity levels as observed in heroin-dependent subjects are a consequence of heroin intake rather than a pre-existing vulnerability trait.
PMCID: PMC3249213  PMID: 21887498
Impulsivity; Heroin; Opiate; Addiction; Delayed reward task; Self-administration
24.  Impulsive choice behavior in four strains of rats: Evaluation of possible models of Attention Deficit/Hyperactivity Disorder 
Behavioural brain research  2012;238:10-22.
Several studies have examined impulsive choice behavior in spontaneously hypertensive rats (SHRs) as a possible pre-clinical model for Attention-Deficit/Hyperactivity Disorder (ADHD). However, this strain was not specifically selected for the traits of ADHD and as a result their appropriateness as a model has been questioned. The present study investigated whether SHRs would exhibit impulsive behavior in comparison to their control strain, Wistar Kyoto (WKY) rats. In addition, we evaluated a strain that has previously shown high levels of impulsive choice, the Lewis (LEW) rats and compared them with their source strain, Wistar (WIS) rats. In the first phase, rats could choose between a Smaller-sooner (SS) reward of 1 pellet after 10 s and a Larger-later (LL) reward of 2 pellets after 30 s. Subsequently, the rats were exposed to increases in LL reward magnitude and SS delay. These manipulations were designed to assess sensitivity to magnitude and delay within the choice task to parse out possible differences in using the strains as models of specific deficits associated with ADHD. The SHR and WKY strains did not differ in their choice behavior under either delay or magnitude manipulations. In comparison to WIS, LEW showed deficits in choice behavior in the delay manipulation, and to a lesser extent in the magnitude manipulation. An examination of individual differences indicated that the SHR strain may not be sufficiently homogeneous in their impulsive choice behavior to be considered as a viable model for impulse control disorders such as ADHD. The LEW strain may be worthy of further consideration for their suitability as an animal model.
PMCID: PMC3513624  PMID: 23085479
impulsive choice; impulse control; differences among rat strains; attention deficit/hyperactivity disorder; individual differences
25.  Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study 
OBJECTIVES—Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance.
METHODS—Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings.
RESULTS—There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%—resulting in 1.7 more hours "on" time a day—compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams.
CONCLUSION—Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.

PMCID: PMC1736320  PMID: 10201413

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