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

Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, Dierckx RA, Elsinga PH, van Waarde A - Psychopharmacology (Berl.) (2015)

Bottom Line: A significant (44-66%) reduction of (11)C-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 D2Rs.The characteristics of dopamine stabilizers may result from the combination of high sigma-1R and low D2R affinity.

View Article: PubMed Central - PubMed

Affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

ABSTRACT

Rationale: Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D2 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.

Objectives: The present study examined sigma-1R and D2R 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 (11)C-SA4503 (sigma-1R) or (11)C-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with (11)C-raclopride. Cerebral (11)C-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V T) calculated by Logan graphical analysis. (11)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 (11)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 D2Rs. 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.

No MeSH data available.


Related in: MedlinePlus

Time-activity curves of radioactivity in rat plasma after injection of the sigma-1 receptor ligand 11C-SA4503 (a, b; note logarithmic x-axis) and areas under the plasma time-activity curve (c). Data are plotted as mean ± SEM
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Fig4: Time-activity curves of radioactivity in rat plasma after injection of the sigma-1 receptor ligand 11C-SA4503 (a, b; note logarithmic x-axis) and areas under the plasma time-activity curve (c). Data are plotted as mean ± SEM

Mentions: Pretreatment of animals with 3 mg/kg pridopidine had very little impact on the clearance of 11C-SA4503-derived radioactivity from plasma (Fig. 4a). However, after treatment of animals with 15 mg/kg pridopidine, the shape of the plasma curve was altered (Fig. 4b). Compared to untreated controls, plasma levels of radioactivity were initially reduced (during the first 5 min after tracer injection) but subsequently increased (between 10 and 60 min). SUV values in Fig. 4 are plotted on a logarithmic x-axis in order to avoid that all data points from the initial frames would overlap. Since AUC takes frame length into account, a small change of radioactivity in a late frame has more impact on the calculated area than a considerable change in an early frame. The area under the plasma curve tended to be increased after pridopidine treatment, by 5 and 33 % at doses of 3 and 15 mg/kg, respectively (Fig. 4c). However, neither of these changes were statistically significant.Fig. 4


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

Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, Dierckx RA, Elsinga PH, van Waarde A - Psychopharmacology (Berl.) (2015)

Time-activity curves of radioactivity in rat plasma after injection of the sigma-1 receptor ligand 11C-SA4503 (a, b; note logarithmic x-axis) and areas under the plasma time-activity curve (c). Data are plotted as mean ± SEM
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537502&req=5

Fig4: Time-activity curves of radioactivity in rat plasma after injection of the sigma-1 receptor ligand 11C-SA4503 (a, b; note logarithmic x-axis) and areas under the plasma time-activity curve (c). Data are plotted as mean ± SEM
Mentions: Pretreatment of animals with 3 mg/kg pridopidine had very little impact on the clearance of 11C-SA4503-derived radioactivity from plasma (Fig. 4a). However, after treatment of animals with 15 mg/kg pridopidine, the shape of the plasma curve was altered (Fig. 4b). Compared to untreated controls, plasma levels of radioactivity were initially reduced (during the first 5 min after tracer injection) but subsequently increased (between 10 and 60 min). SUV values in Fig. 4 are plotted on a logarithmic x-axis in order to avoid that all data points from the initial frames would overlap. Since AUC takes frame length into account, a small change of radioactivity in a late frame has more impact on the calculated area than a considerable change in an early frame. The area under the plasma curve tended to be increased after pridopidine treatment, by 5 and 33 % at doses of 3 and 15 mg/kg, respectively (Fig. 4c). However, neither of these changes were statistically significant.Fig. 4

Bottom Line: A significant (44-66%) reduction of (11)C-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 D2Rs.The characteristics of dopamine stabilizers may result from the combination of high sigma-1R and low D2R affinity.

View Article: PubMed Central - PubMed

Affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

ABSTRACT

Rationale: Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D2 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.

Objectives: The present study examined sigma-1R and D2R 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 (11)C-SA4503 (sigma-1R) or (11)C-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with (11)C-raclopride. Cerebral (11)C-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V T) calculated by Logan graphical analysis. (11)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 (11)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 D2Rs. 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.

No MeSH data available.


Related in: MedlinePlus