posted on 2020-02-17, 17:05authored byAnna Schildt, Erik F.J. de Vries, Antoon T.M. Willemsen, Bruno Lima Giacobbo, Rodrigo Moraga-Amaro, Jürgen W.A. Sijbesma, Aren van Waarde, Vesna Sossi, Rudi A.J.O. Dierckx, Janine Doorduin
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 (Ki) 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 p > 0.07, Cohen’s d 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 p = 0.022, Cohen’s d = 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 p = 0.4, Cohen’s d = 1.77) and raclopride
(adjusted p = 0.052, Cohen’s d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen’s d 0.63–0.74). Raclopride treatment nonsignificantly
increased Ki in the striatum 1.3-fold
compared to control rats (adjusted p = 0.1, Cohen’s d = 1.1) while it reduced Ki in the cerebellum by 28% (adjusted p = 0.0004,
Cohen’s d = 2.2) compared to control rats.
Pretreatment with haloperidol led to a nonsignificant reduction in Ki in the striatum (10%, adjusted p = 1, Cohen’s d = 0.44) and a 40–50%
lower Ki than controls in all other brain
regions (adjusted p < 0.0005, Cohen’s d = 3.3–4.7). The changes in Ki 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.