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

Abstract

Background In 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). Results Systemic 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. Conclusion The 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.

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

“…It is also important to note that quinpirole, used in the present study, is a D2/D3 agonist, thus TP-10 efficacy in this model could reflect modulation of D3 effects on sensorimotor gating as well as D2. D3 receptor activation in the striatum also disrupts PPI (Chang et al 2012), thus TP-10 effects in this experiment may have been due to attenuation of either D2 or D3 signaling effects.…”

Effects of the 5HT2C antagonist SB242084 on the pramipexole-induced potentiation of water contrafreeloading, a putative animal model of compulsive behavior

“…We have previously shown that QNP-induced prepulse inhibition (PPI) disruption parallels its hyperdipsic effect (De Carolis et al 2010). Here, PPX dosage was chosen according to studies performed by Chang and collaborators on PPI (Chang et al 2010(Chang et al , 2011(Chang et al , 2012. Free access to water was provided through water-filled 200-mL plastic bottles with metal spouts.…”

Dexpramipexole Is Ineffective in Two Models of ALS Related Neurodegeneration

“…These characteristics were thought to make it a reasonable candidate for mechanistic, preclinical, and clinical studies in ALS. [17] , [19] , [21] , [22] …”

“…In both cases, we aimed to expose the test systems to drug levels approximating those achieved and reported in human Phase II clinical investigations. [21] …”