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

Pramipexole (PPX) is a D(2) and D(3) 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(3), but not D(2) dopamine receptors, in the nucleus accumbens. However, the behavioral effects of PPX and RES were not reduced by acute treatments with the D(2)/D(3) receptor antagonist raclopride (0.01-0.05 mg/kg, SC), the highly selective D(2) receptor antagonist L-741,626 (0.1-1 mg/kg, SC) or the D(3) 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(2) or D(3) receptor activation.