Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses.

Sahlholm, Kristoffer; Sijbesma, Jurgen; Maas, Bram; Kwizera, Chantal; Marcellino, Daniel; Ramakrishnan, Nisha; Dierckx, Rudi; Elsinga, Philip; Waarde, Aren

Rationale: Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D receptor (DR) antagonists or weak partial agonists and may have pro-mnemonic and neuroprotective effects. The mechanism underlying their stimulatory and neuroprotective actions is unknown but could involve sigma-1R binding. Objectives: The present study examined sigma-1R and DR occupancy by the dopamine stabilizer pridopidine (ACR16) at behaviorally relevant doses in living rats. Methods: Rats were administered 3 or 15 mg/kg pridopidine, or saline, before injection of the radiotracer C-SA4503 (sigma-1R) or C-raclopride (DR). Some animals received 60 mg/kg pridopidine and were only scanned with C-raclopride. Cerebral C-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume ( V) calculated by Logan graphical analysis. C-raclopride binding was quantified using striatum-to-cerebellum ratios and binding potentials calculated with a simplified reference tissue model. Results: Cunningham-Lassen plots indicated sigma-1R occupancies of 57 ± 2 and 85 ± 2 % after pretreatment of animals with 3 and 15 mg/kg pridopidine. A significant (44-66 %) reduction of C-raclopride binding was only observed at 60 mg/kg pridopidine. Conclusions: At doses shown to elicit neurochemical and behavioral effects, pridopidine occupied a large fraction of sigma-1Rs and a negligible fraction of DRs. Significant DR occupancy was only observed at a dose 20-fold higher than was required for sigma-1R occupancy. The characteristics of dopamine stabilizers may result from the combination of high sigma-1R and low DR affinity.

CATALEPSY; DOPAMINE receptors; DRUG dosage; STABILIZING agents; NEUROPROTECTIVE agents; LABORATORY rats

Psychopharmacology, 2015, Vol 232, Issue 18, p3443

0033-3158

Academic Journal

10.1007/s00213-015-3997-8