Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats

BackgroundIn rats, prepulse inhibition (PPI) of acoustic startle is disrupted by systemic administration of dopaminergic agonists, such as the dopamine D3 receptor (D3R)-preferential agonist pramipexole (PPX). PPX has D3R-active (S) and -inactive (R) stereoisomers. Here, we tested the neuroanatomical and stereochemical selectivity of PPX effects on PPI.Methods(S)-PRA or (R)-PRA (0, 0.47, 1.42, 4.73 μmol/kg) was injected sc 15 min prior to PPI testing in adult male Sprague Dawley rats. In separate rats, (S)-PPX (0, 3, 10 μg/0.5 μl/side, ic) was infused into the nucleus accumbens (NAc), caudodorsal striatum (CS), or olfactory tubercle/Islands of Calleja (ICj) 15 min prior to PPI testing. D3R expression in these brain regions was assessed using quantitative rt-PCR. The PPI-disruptive effects of systemic (S)-PPX were also tested after pretreatment with the D3R-selective antagonist, U99194 (10 mg/kg).ResultsSystemic administration of PPX stereoisomers demonstrated a dose-dependent effect of (S)-PPX on PPI, while (R)-PPX had no effect on PPI. PPX decreased PPI when infused into the NAc and ICj, but not the CS. Quantitative rt-PCR revealed D3R expression in ICj > NAc > CS. The PPI-disruptive effects of PPX were prevented by U99194.ConclusionThe PPI-reducing effects of PPX are stereospecific for the D3R-active (S)-isomer, neuroanatomically preferential for the D3R-rich ventral vs. D3R poor caudodorsal striatum, and prevented by pharmacologic D3R blockade. These findings are consistent with the conclusion that PPX disrupts PPI via stimulation of mesolimbic D3Rs.

► Pramipexole (PPX) effects on prepulse inhibition (PPI) are stereospecific to the (S) isomer.
► PPI is disrupted by (S)-PPX infusion into the nucleus accumbens and Islands of Calleja, but not the dorsal posterior striatum.
► DA D3 receptor expression in Islands of Calleja > nucleus accumbens > posterior striatum by rt-PCR.
► The PPI-disruptive effects of (S)-PPX are significantly opposed by the D3 receptor-preferential antagonist, U99194.