[¹¹C]‐(+)‐PHNO PET imaging of dopamine D_2/3 receptors in Parkinson's disease with impulse control disorders

Abstract

Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [¹¹C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [¹¹C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [¹¹C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [¹¹C]-(+)-PHNO binding is associated with D2 receptor levels, [¹¹C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved.

Current drug treatments targeting dopamine D3 receptor

“…A number of studies have investigated D3R expression in brain of subjects with SUD through PET studies provide evidence of D3R upregulation in SUD, they have not indicated, so far, D3R changes associated to impulse control disorders. In PD patients with impulse control disorders following treatment with L-DOPA or DR agonists, there is no change in striatal [ 11 C]-(+)-PHNO (Payer et al, 2015). Consistently, in pathological gambling, a form of behavioral addiction associated with elevated impulsivity, no significant differences have been found in the same brain areas (Boileau et al, 2013).…”

Imaging the D3 dopamine receptor across behavioral and drug addictions: Positron emission tomography studies with [11C]-(+)-PHNO

“…In cocaine-dependence, we found significant correlations between D 3 availability (measured as [ 11 C]-(+ )-PHNO binding in the substantia nigra) and risky decision-making (number of risky choices on the Game of Dice task), as well as attention and inhibitory control deficits (errors on the Continuous Performance Task) (Payer et al, 2013). Similarly, in pathological gambling we reported that despite D 3 receptor levels in the normal range (in both healthy pathological gamblers and patients with Parkinson's Disease with pathological gambling) (Boileau et al, 2013a;Payer et al, 2015), higher D 3 levels related to greater self-reported impulsive personality (Eysenck questionnaire) and gambling severity (south oaks gambling scale score). Together, these findings implicate D 3 receptor levels in impulsive and risky decision-making, indicating a functional relevance of the observed D 3 upregulation in humans (Boileau et al, 2012a(Boileau et al, , 2013b.…”

Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective drugs

“…These data complement previous observations (Weiss and Marsh, 2012) and provide support the suggestion that D3-preferential D2/D3 agonists are associated with impulse control disorders and require a careful assessment of patient predisposing factor before advice for the treatment (Connelly and Lang 2014). However, a recent imaging study visualising D3 receptors in PD patients with or without impulse control disorders showed no difference in D3 receptor density (Payer et al, 2015), suggesting that a functional hyper-responsivity (that does not require an increased density of receptors) could be implicated.…”