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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

Total distribution volume (VT) of 11C-SA4503 in different brain regions estimated using Logan graphical analysis (a) and Cunningham-Lassen plot of sigma-1 receptor occupancy by pridopidine (b). Each data point in the plot represents an individual brain region
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Fig6: Total distribution volume (VT) of 11C-SA4503 in different brain regions estimated using Logan graphical analysis (a) and Cunningham-Lassen plot of sigma-1 receptor occupancy by pridopidine (b). Each data point in the plot represents an individual brain region

Mentions: Logan graphical analysis was performed to estimate VT in the whole brain and in different brain regions. Increasing doses of pridopidine produced a dose-dependent reduction in VT for all regions investigated (Fig. 6a). The reduction was statistically significant at either dose. The Lassen plot as modified by Cunningham was used to estimate receptor occupancy and VND (Fig. 6b). Receptor occupancy was 56.7 ± 2.3 % at 3 mg/kg and 84.5 ± 1.7 % at 15 mg/kg. The VND calculated as an average of the two doses administered was 3.99. Since the average whole brain VT (after metabolite correction) was 14.39, the specific binding fraction of 11C-SA4503 in rat brain was >72 %, very similar to the value of 75 % previously reported using the same method in Wistar-Hannover rats (Ramakrishnan et al. 2014).Fig. 6


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)

Total distribution volume (VT) of 11C-SA4503 in different brain regions estimated using Logan graphical analysis (a) and Cunningham-Lassen plot of sigma-1 receptor occupancy by pridopidine (b). Each data point in the plot represents an individual brain region
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4537502&req=5

Fig6: Total distribution volume (VT) of 11C-SA4503 in different brain regions estimated using Logan graphical analysis (a) and Cunningham-Lassen plot of sigma-1 receptor occupancy by pridopidine (b). Each data point in the plot represents an individual brain region
Mentions: Logan graphical analysis was performed to estimate VT in the whole brain and in different brain regions. Increasing doses of pridopidine produced a dose-dependent reduction in VT for all regions investigated (Fig. 6a). The reduction was statistically significant at either dose. The Lassen plot as modified by Cunningham was used to estimate receptor occupancy and VND (Fig. 6b). Receptor occupancy was 56.7 ± 2.3 % at 3 mg/kg and 84.5 ± 1.7 % at 15 mg/kg. The VND calculated as an average of the two doses administered was 3.99. Since the average whole brain VT (after metabolite correction) was 14.39, the specific binding fraction of 11C-SA4503 in rat brain was >72 %, very similar to the value of 75 % previously reported using the same method in Wistar-Hannover rats (Ramakrishnan et al. 2014).Fig. 6

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