Effect of Dopamine D₂ Receptor Antagonists on [¹⁸F]-FEOBV Binding

The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson’s disease has been well established. Here, D₂ receptor antagonists were used to assess changes in [¹⁸F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (<i>K</i>_i) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [¹⁸F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted <i>p</i> > 0.07, Cohen’s <i>d</i> 0.28–1.89) while the area-under-the-curve (AUC) of the parent fraction of [¹⁸F]-FEOBV was significantly higher after haloperidol treatment (adjusted <i>p</i> = 0.022, Cohen’s <i>d</i> = 2.51) than in controls. Compared to controls, the AUC of [¹⁸F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted <i>p</i> = 0.4, Cohen’s <i>d</i> = 1.77) and raclopride (adjusted <i>p</i> = 0.052, Cohen’s <i>d</i> = 1.49) treatment, respectively. No changes in the AUC of [¹⁸F]-FEOBV were found in the cerebellum (Cohen’s <i>d</i> 0.63–0.74). Raclopride treatment nonsignificantly increased <i>K</i>_i in the striatum 1.3-fold compared to control rats (adjusted <i>p</i> = 0.1, Cohen’s <i>d</i> = 1.1) while it reduced <i>K</i>_i in the cerebellum by 28% (adjusted <i>p</i> = 0.0004, Cohen’s <i>d</i> = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in <i>K</i>_i in the striatum (10%, adjusted <i>p</i> = 1, Cohen’s <i>d</i> = 0.44) and a 40–50% lower <i>K</i>_i than controls in all other brain regions (adjusted <i>p</i> < 0.0005, Cohen’s <i>d</i> = 3.3–4.7). The changes in <i>K</i>_i induced by the selective D₂ receptor antagonist raclopride can in part be quantified using [¹⁸F]-FEOBV PET imaging. Haloperidol, a nonselective D₂/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [¹⁸F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [¹⁸F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.