Objective: To determine whether pramipexole (PPX) differentially upregulates AMPA receptor trafficking in limbic vs. motor striatal regions of rats.

Background: Impulse control disorders (ICD) are a side effect of PPX, a dopamine agonist, used in Parkinson’s disease and restless leg syndrome. Mechanisms that underlie these disorders are poorly understood. PPX has a high affinity for D2 and D3 receptors (D2/D3R). These receptors are expressed throughout the forebrain, but D3R are higher in limbic regions implicated in ICD, whereas D2R are higher in basal ganglia regions involved in motor control. Increases in limbic striatal AMPA receptor (AMPAR)-mediated synaptic strength is associated with addictions, which often involve impulse control. D2R/D3R signaling can involve Akt/GSK3β, and GSK3β promotes insertion of AMPAR into cytosolic membranes to strengthen glutamatergic synapses. We hypothesized PPX-activation of D3R will alter Akt/GSK3β and AMPAR trafficking in limbic brain regions involved in addiction (nucleus accumbens), but not in motor-related basal ganglia regions (dorsal striatum).

Methods: Rats were administered saline or PG01037 (D3R antagonist); 30min later, saline or PPX was administered. One hour later, they were killed and striatal regions were extracted. Western blot protocols determined tissue levels of Akt/GSK3β, and surface and intracellular levels of AMPAR subunits (GluA1, GluA2). Data were analyzed using a one-way ANOVA followed by a post hoc Newman-Keuls test.

Results:  PPX significantly reduced the ratio of pAkt (active)/Akt (total) and pGSK3β (inactive)/GSK3β (total) and increased the surface/intracellular (S/I) ratio for GluA1 and GluA2 in the nucleus accumbens. These effects were reversed by PG01037. In the dorsal striatum, no change occurred in pAkt/Akt, pGSK3β/GSK3β or GluA2 S/I. Unexpectedly, PG01037 decreased GluA1 S/I, (likely reflecting blockade of endogenous dopamine activation of D3R).

Conclusions: PPX upregulates AMPA receptor trafficking to the cytosolic membrane in nucleus accumbens (i.e., limbic striatum) via D3R-mediated Akt/GSK3β signaling, but this does not occur in basal ganglia striatum. This may be a mechanism that underlies dopamine agonist-induced ICD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/basal-ganglia-and-limbic-striatal-regions-are-differentially-affected-by-pramipexole-d3-receptor-mediated-changes-in-markers-of-synaptic-strength/