Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers

Psychopharmacology Section, University of Nottingham, Division of Psychiatry, Nottingham, UK.
British Journal of Clinical Pharmacology (Impact Factor: 3.88). 12/2007; 64(5):591-602. DOI: 10.1111/j.1365-2125.2007.02938.x
Source: PubMed


To investigate the effects of the D2-receptor agonist pramipexole with and without the co-administration of the peripherally acting D2-receptor antagonist domperidone on measures of alertness, autonomic and endocrine function.
Sixteen male volunteers participated in four weekly sessions of pramipexole 0.5 mg, domperidone 40 mg, their combination, and placebo administered according to a balanced, double-blind design. Alertness (visual analogue scales (VAS), critical flicker fusion frequency, pupillographic sleepiness test), autonomic (pupil diameter, light and darkness reflexes, blood pressure, heart rate, salivation, temperature) and endocrine (prolactin, thyroid-stimulating hormone (TSH), growth hormone (GH)) functions were assessed. Data were analyzed with anova with multiple comparisons.
The pre-post treatment changes in VAS alertness were reduced by pramipexole with and without domperidone (mean difference from placebo (95% confidence interval), mm): pramipexole -15.75 (-23.38, -8.13), combination -11.84 (-20.77, -2.91). Treatment condition significantly affected pupil diameter measured in different ways (resting pupil diameter (F(3,45) = 8.39, P < 0.001), initial diameter of the light reflex response (F(3,42) = 3.78, P < 0.05), and light (F(3,45) = 5.21, P < 0.005) and dark (F(3,45) = 3.36, P < 0.05) diameters of the darkness reflex response). Pramipexole without domperidone consistently increased pupil diameter on all measures (P < 0.05), whereas with domperidone only the increase in resting and dark diameters reached significance. Pramipexole reduced light reflex amplitude and increased latency, whereas the combination affected latency only. Concentrations of prolactin and TSH were increased by domperidone. Pramipexole reduced prolactin and increased GH concentrations.
The attenuation of the central pupillary effects of pramipexole by domperidone indicates that domperidone had access to some central D2-receptors.

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Available from: Ruihua Hou, Oct 07, 2015
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    • "In the current study, we report tentative findings suggesting that pramipexole reduced the learning rate rather than affecting the reward sensitivity, which might correspond to a direct reduction in the signal reported by phasic DA. Although pramipexole is a non-ergot D 2/D3agonist (and is clinically used as such in Parkinson’s disease, restless leg syndrome, and occasionally in treatment-resistant MDD), it has previously been found to have behavioural effects of a DA antagonist at the low doses (0.5 mg) used in our dataset [72-74]. Similarly, low doses of the D 2 agonist cabergoline have been found to specifically reduce reward go learning [75]. "
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    ABSTRACT: Background Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. Methods Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. Results MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. Conclusion Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior.
    Biology of Mood and Anxiety Disorders 06/2013; 3(1):12. DOI:10.1186/2045-5380-3-12
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    • "In terms of limitations, it should be noted that the peripheral D 2 antagonist domperidone was administered on both testing days. Whilst domperidone is generally assumed not to cross the blood–brain barrier, there is some evidence that the effects of domperidone and pramipexole differ from pramipexole alone (Samuels et al., 2007). However, domperidone is useful for preventing nausea and sickness clinically (Parkes, 1986) and proved effective for these purposes in this study. "
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    ABSTRACT: Background: A reduction in reward responsivity and an increase in temporal discounting of rewards are both evident in smokers during acute abstinence compared to satiation. However, it is not yet known whether these processes can be modulated pharmacologically in smokers, other than with nicotine or tobacco. Methods: A double-blind placebo controlled crossover design assessed the effects of 0.5 mg pramipexole, a dopamine D₂/D₃ agonist, in smokers following 2 h of abstinence. Reward responsivity was measured using an effort-based card sorting task. Temporal discounting of monetary reward was assessed using Area Under the Curve (AUC) analysis, and affective and subjective effects were indexed. Results: On placebo, smokers showed an equivalent speed of card sorting when a financial incentive was provided compared to when it was not. Conversely, more cards were sorted under rewarded compared to non-rewarded trials after pramipexole, indicating an improvement in reward responsivity. Temporal discounting of monetary reward was not affected by pramipexole. Drug treatment also decreased positive affect and increased drowsiness. Conclusions: A single dose of pramipexole can enhance effort-based reward responsivity, but does not alter temporal discounting in smokers. These findings highlight pharmacological correlates of reward processing deficits in nicotine dependence and offer potential targets for their treatment.
    Drug and alcohol dependence 11/2012; 130(1-3). DOI:10.1016/j.drugalcdep.2012.10.016 · 3.42 Impact Factor
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    British Journal of Clinical Pharmacology 03/2008; 65(2):154-7. DOI:10.1111/j.1365-2125.2008.03101.x · 3.88 Impact Factor
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