The adverse effects of pramipexole on probability discounting are not reversed by acute D 2 or D 3 receptor antagonism

• Published in: European neuropsychopharmacology 2020-03, Vol.32, p.104
• Main Authors: Orrù, Marco, Strathman, Hunter J, Floris, Gabriele, Scheggi, Simona, Levant, Beth, Bortolato, Marco
• Format: Article
• Language: English
• Subjects: Animals; Delay Discounting - drug effects; Delay Discounting - physiology; Discrimination Learning - drug effects; Discrimination Learning - physiology; Dopamine Agonists - toxicity; Dopamine D2 Receptor Antagonists - pharmacology; Male; Pramipexole - toxicity; Rats; Rats, Long-Evans; Reaction Time - drug effects; Reaction Time - physiology; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - antagonists & inhibitors; Receptors, Dopamine D3 - metabolism
• ISSN: 1873-7862
• DOI: 10.1016/j.euroneuro.2020.01.005

Pramipexole (PPX) is a D and D 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 D , but not D dopamine receptors, in the nucleus accumbens. However, the behavioral effects of PPX and RES were not reduced by acute treatments with the D /D receptor antagonist raclopride (0.01-0.05 mg/kg, SC), the highly selective D receptor antagonist L-741,626 (0.1-1 mg/kg, SC) or the D 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 D or D receptor activation.