GPR52 agonists attenuate ropinirole-induced preference for uncertain outcomes.

Abstract

Dopamine D2/3 receptor agonists are less likely to trigger dyskinesias than l-dopa while still offering relief from the motor symptoms of Parkinson’s disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful. G-protein-coupled receptor 52 (GPR52) is an orphan Gs-protein-coupled receptor that is coexpressed with striatal D2 receptors. Activating GPR52 attenuates behaviors associated with increased striatal dopamine release without altering basal function. Iatrogenic gambling disorder may be mediated, at least partly, by striatal dopamine signaling. We therefore investigated whether 2 potent small-molecule GPR52 agonists (BD442618, BD502657) could block the increase in preference for uncertain outcomes caused by acute d-amphetamine and chronic ropinirole, without altering baseline choice patterns. In the rat betting task (rBT), subjects choose between a guaranteed reward (the “wager”) versus the 50:50 chance of double the wager or nothing. Although wager size varies across trial blocks, both options are constantly matched for expected value. The effects of BD442618 on the rBT were acutely assessed alone or in combination with d-amphetamine and subsequently in combination with chronic ropinirole. The latter experiment was then repeated with BD502657. BD442618 did not alter baseline decision making but attenuated the increase in preference for uncertainty caused by both acute amphetamine and chronic ropinirole administration. Similarly, BD502657 abrogated chronic ropinirole’s effects. These data provide the first evidence that GPR52 agonists may be useful in treating iatrogenic gambling disorder or other conditions hallmarked by hyperdopaminergic states.

Impulse Control Disorders in Parkinson’s Disease: From Bench to Bedside

“…Using PDT, pramipexole increased preference for the large reinforcer by approximately 30-45% even at the greatest uncertainty levels in PD-induced rats (Rokosik and Napier, 2012). Even when the expected value of both options remains the same, such as when the uncertain outcome is twice the size as the guaranteed reward but only delivered on 50% of trials, chronic ropinirole administration increased choice for the large-but-uncertain outcome (Tremblay et al, 2017;Russell et al, 2020). The size of the effect was comparable in lesioned and non-lesioned rats.…”

“…However, naltrexone (Papay et al, 2014), various SSRIs (Bosco et al, 2012;Jeon and Bortolato, 2020), amantadine (Thomas et al, 2010;Weintraub et al, 2010b), and several atypical antipsychotics and glutamatergic modulators (Jeon and Bortolato, 2020) have also been reported to have no or negative impact on PD + ICD. In rodent PD models, positive effects have been observed with agonists of G proteincoupled receptor 52 (Russell et al, 2020); propranolol, a βadrenoceptor antagonist (Cocker et al, 2019); and mirtazapine, an atypical antidepressant (Holtz et al, 2016). Whether nonpharmacological interventions such as deep brain stimulation (DBS) ameliorates or worsens ICRBs in PD patients is still debated.…”

Innovative Therapeutic Approaches for Huntington’s Disease: From Nucleic Acids to GPCR-Targeting Small Molecules

“…GPR52 is expressed in dopamine D2 receptor (D2R)-expressing MSNs of the basal ganglia, while largely expressed in dopamine D1 receptor (D1R)-expressing neurons in the medial prefrontal cortex (Figure 1). GPR52 represents a promising therapeutic target for the treatment of not only HD but also Parkinson's disease (Russell et al, 2021), schizophrenia, and several other psychiatric disorders (Komatsu et al, 2014). For instance, GPR52 agonists are well-known to inhibit D2R signaling and activate D1R/NMDA receptors via intracellular cAMP accumulation, demonstrating antipsychoticlike and procognitive effects in rodents (Setoh et al, 2014;Komatsu, 2015;Nishiyama et al, 2017a;Wang et al, 2020).…”

Exploring orphan GPCRs in neurodegenerative diseases

“…GPR52 signaling via cAMP has been implicated in opposing D2 signaling in the striatum while stimulating D1/NMDA function in the frontal cortex (Russell et al, 2021). However, the effectiveness of GPR52 agonism in modulating D2/3 receptor signaling outside of the striatum may be limited by lower expression levels (Rahman et al, 2022).…”