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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

Fraction of plasma radioactivity representing intact parent compound after injection of 11C-SA4503. Each data point represents the mean value of two rats
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Fig5: Fraction of plasma radioactivity representing intact parent compound after injection of 11C-SA4503. Each data point represents the mean value of two rats

Mentions: Tracer metabolism was dose-dependently accelerated after treatment of rats with various doses of pridopidine (Fig. 5). While 55 % of the parent tracer remained unchanged at 60 min in saline-treated rats, only 39 and 33 % remained in the 3 and 15 mg/kg groups.Fig. 5


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)

Fraction of plasma radioactivity representing intact parent compound after injection of 11C-SA4503. Each data point represents the mean value of two rats
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Fraction of plasma radioactivity representing intact parent compound after injection of 11C-SA4503. Each data point represents the mean value of two rats
Mentions: Tracer metabolism was dose-dependently accelerated after treatment of rats with various doses of pridopidine (Fig. 5). While 55 % of the parent tracer remained unchanged at 60 min in saline-treated rats, only 39 and 33 % remained in the 3 and 15 mg/kg groups.Fig. 5

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