The adverse effects of pramipexole on probability discounting are not reversed by acute D2 or D3 receptor antagonism.

Pramipexole (PPX) is a D2 and D3 dopamine receptor agonist approved for clinical use, which is associated with a higher risk of impulse-control disorders. Using a rat model, we recently found that low doses of the monoamine-depleting agent reserpine (RES; 1 mg/kg/day, SC) dramatically increased the untoward effects of PPX (0.3 mg/kg/day, SC) on probability discounting, a key impulsivity function. To further understand the neurobehavioral mechanisms underlying these effects, we first tested whether the combination of PPX and RES may lead to a generalized enhancement in risk taking, as tested in the suspended wire-beam paradigm. The association of RES and PPX did not augment the proclivity of rats to cross the bridge in order to obtain a reward, suggesting that the effects of RES and PPX on probability discounting do not reflect a generalized increase in impulsivity. We then studied what receptors mediate the effects of PPX in RES-treated rats. The combination of RES and PPX increased membrane expression and binding of D3, but not D2 dopamine receptors, in the nucleus accumbens. However, the behavioral effects of PPX and RES were not reduced by acute treatments with the D2/D3 receptor antagonist raclopride (0.01-0.05 mg/kg, SC), the highly selective D2 receptor antagonist L-741,626 (0.1-1 mg/kg, SC) or the D3 receptor antagonists GR 103691 (0.1-0.3 mg/kg, SC) and SB 277011A (1-10 mg/kg, SC). These findings collectively suggest that the effects of PPX in probability discounting do not reflect generalized enhancements in impulsivity or acute dopamine D2 or D3 receptor activation.

Sleep disturbance by pramipexole is modified by Meis1 in mice.

Meis homeobox 1 (Meis1) is a transcription factor functioning in the development of the nervous system and the cardiovascular system. Both common and rare variants within the gene have been associated with restless legs syndrome (RLS), while its association with symptoms of insomnia has also been discovered recently. RLS is associated with sleep disturbances, and while Meis1 haploinsufficiency is one of the most promising strategies for an RLS animal model, sleep phenotyping of Meis1 knockout mice has never been conducted. We report a detailed sleep analysis of heterozygous Meis1 knockout mice and challenge it with pramipexole, a dopamine agonist used in the treatment of RLS. At baseline, the Meis1-haploinsufficient mice had a trend towards lower delta power in the electroencephalogram (EEG) during sleep compared to the wild-type littermates, possibly indicating reduced sleep quality, but not sleep fragmentation. Pramipexole had a sleep disrupting effect in both genotype groups. In addition, it exerted differential effects on the EEG power spectra of the two mouse lines, remarkably elevating the theta power of the mutant mice during recovery more than that of the wild-types. In conclusion, Meis1 haploinsufficiency seems to have only a modest effect on sleep, but the gene may interact with the sleep-disrupting effect of dopamine agonists.