Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D-2 receptor (D2R) 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.
The present study examined sigma-1R and D2R occupancy by the dopamine stabilizer pridopidine (ACR16) at behaviorally relevant doses in living rats.
Rats were administered 3 or 15 mg/kg pridopidine, or saline, before injection of the radiotracer C-11-SA4503 (sigma-1R) or C-11-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with C-11-raclopride. Cerebral C-11-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V (T)) calculated by Logan graphical analysis. C-11-raclopride binding was quantified using striatum-to-cerebellum ratios and binding potentials calculated with a simplified reference tissue model.
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-11-raclopride binding was only observed at 60 mg/kg pridopidine.
At doses shown to elicit neurochemical and behavioral effects, pridopidine occupied a large fraction of sigma-1Rs and a negligible fraction of D(2)Rs. Significant D2R 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 D2R affinity.
- Kinetic analysis
- Receptor occupancy
- STABILIZERS PRIDOPIDINE