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Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures

View Article: PubMed Central - PubMed

ABSTRACT

Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL11,939 and another selective 5-HT2A antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT2C agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT2C antagonist SB 242984. In summary, 5-HT2ARs and 5-HT2CRs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT2R subtypes might be potential novel anti-absence drugs.

No MeSH data available.


Effect of TCB-2, CP-809,101 and lorcaserin on interictal EEG. (A1) TCB-2 (3 mg/kg, n = 6) significantly reduced EEG power in the alpha (8–12 Hz) and gamma (30–80 Hz) bands compared to vehicle (n = 7). (A2) Mean normalized power change at 40 min compared to the relative time point in the vehicle injected animals (top) and raw EEG spectrum at 40 min compared to pre-drug (bottom). (B1) CP-809,101 (10 mg/kg, n = 6) significantly increased EEG power in the delta (1–4 Hz) and decreased power in the gamma band (30–80 Hz) compared to vehicle (n = 8). (B2) Mean normalized power change at 60 min compared to equivalent time point in the vehicle injected animals (top) and raw EEG spectrum at 60 min compared to pre-drug (bottom). (C1) In the lorcaserin treated animals (10 mg/kg) no individual point reached statistical significance after post-hoc testing, although a trend for an effect in the delta and gamma bands is visible at 40 min (C2). All values are normalized to the control period (−40 to 0 min), and are expressed as a percentage of their respective vehicle group. Values represent mean ± SEM. Asterisks indicate p < 0.05 for a given time bin in the treatment group vs the corresponding time bin in the vehicle group (two-way ANOVA, Sidak's multiple comparison test).
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fig4: Effect of TCB-2, CP-809,101 and lorcaserin on interictal EEG. (A1) TCB-2 (3 mg/kg, n = 6) significantly reduced EEG power in the alpha (8–12 Hz) and gamma (30–80 Hz) bands compared to vehicle (n = 7). (A2) Mean normalized power change at 40 min compared to the relative time point in the vehicle injected animals (top) and raw EEG spectrum at 40 min compared to pre-drug (bottom). (B1) CP-809,101 (10 mg/kg, n = 6) significantly increased EEG power in the delta (1–4 Hz) and decreased power in the gamma band (30–80 Hz) compared to vehicle (n = 8). (B2) Mean normalized power change at 60 min compared to equivalent time point in the vehicle injected animals (top) and raw EEG spectrum at 60 min compared to pre-drug (bottom). (C1) In the lorcaserin treated animals (10 mg/kg) no individual point reached statistical significance after post-hoc testing, although a trend for an effect in the delta and gamma bands is visible at 40 min (C2). All values are normalized to the control period (−40 to 0 min), and are expressed as a percentage of their respective vehicle group. Values represent mean ± SEM. Asterisks indicate p < 0.05 for a given time bin in the treatment group vs the corresponding time bin in the vehicle group (two-way ANOVA, Sidak's multiple comparison test).

Mentions: In addition to modifying ASs, both at the EEG and behavioral level, the highest doses of TCB-2 (3 mg/kg) and CP-809,101 (10 mg/kg) were also able to produce significant modifications of the power of different frequency bands in the interictal EEG (Fig. 4). TCB-2 induced a long-lasting decrease in the power of the gamma (26.4± 4.4% mean reduction, p < 0.001) and alpha (28.0 ± 8.5% mean reduction, p < 0.001 vs vehicle) frequency bands. CP-809,101 elicited a reduction in the gamma band power (26.1 ± 21.5%, mean decrease, p < 0.05) and a drastic increase in the delta band (64.5 ± 23.0% mean increase, p < 0.001). Finally, a trend for an increase in the delta band power and a decrease in the alpha band was apparent in the interictal EEG following the injection of 10 mg/kg lorcaserin although no individual time epoch reached statistical significance.


Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures
Effect of TCB-2, CP-809,101 and lorcaserin on interictal EEG. (A1) TCB-2 (3 mg/kg, n = 6) significantly reduced EEG power in the alpha (8–12 Hz) and gamma (30–80 Hz) bands compared to vehicle (n = 7). (A2) Mean normalized power change at 40 min compared to the relative time point in the vehicle injected animals (top) and raw EEG spectrum at 40 min compared to pre-drug (bottom). (B1) CP-809,101 (10 mg/kg, n = 6) significantly increased EEG power in the delta (1–4 Hz) and decreased power in the gamma band (30–80 Hz) compared to vehicle (n = 8). (B2) Mean normalized power change at 60 min compared to equivalent time point in the vehicle injected animals (top) and raw EEG spectrum at 60 min compared to pre-drug (bottom). (C1) In the lorcaserin treated animals (10 mg/kg) no individual point reached statistical significance after post-hoc testing, although a trend for an effect in the delta and gamma bands is visible at 40 min (C2). All values are normalized to the control period (−40 to 0 min), and are expressed as a percentage of their respective vehicle group. Values represent mean ± SEM. Asterisks indicate p < 0.05 for a given time bin in the treatment group vs the corresponding time bin in the vehicle group (two-way ANOVA, Sidak's multiple comparison test).
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Related In: Results  -  Collection

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fig4: Effect of TCB-2, CP-809,101 and lorcaserin on interictal EEG. (A1) TCB-2 (3 mg/kg, n = 6) significantly reduced EEG power in the alpha (8–12 Hz) and gamma (30–80 Hz) bands compared to vehicle (n = 7). (A2) Mean normalized power change at 40 min compared to the relative time point in the vehicle injected animals (top) and raw EEG spectrum at 40 min compared to pre-drug (bottom). (B1) CP-809,101 (10 mg/kg, n = 6) significantly increased EEG power in the delta (1–4 Hz) and decreased power in the gamma band (30–80 Hz) compared to vehicle (n = 8). (B2) Mean normalized power change at 60 min compared to equivalent time point in the vehicle injected animals (top) and raw EEG spectrum at 60 min compared to pre-drug (bottom). (C1) In the lorcaserin treated animals (10 mg/kg) no individual point reached statistical significance after post-hoc testing, although a trend for an effect in the delta and gamma bands is visible at 40 min (C2). All values are normalized to the control period (−40 to 0 min), and are expressed as a percentage of their respective vehicle group. Values represent mean ± SEM. Asterisks indicate p < 0.05 for a given time bin in the treatment group vs the corresponding time bin in the vehicle group (two-way ANOVA, Sidak's multiple comparison test).
Mentions: In addition to modifying ASs, both at the EEG and behavioral level, the highest doses of TCB-2 (3 mg/kg) and CP-809,101 (10 mg/kg) were also able to produce significant modifications of the power of different frequency bands in the interictal EEG (Fig. 4). TCB-2 induced a long-lasting decrease in the power of the gamma (26.4± 4.4% mean reduction, p < 0.001) and alpha (28.0 ± 8.5% mean reduction, p < 0.001 vs vehicle) frequency bands. CP-809,101 elicited a reduction in the gamma band power (26.1 ± 21.5%, mean decrease, p < 0.05) and a drastic increase in the delta band (64.5 ± 23.0% mean increase, p < 0.001). Finally, a trend for an increase in the delta band power and a decrease in the alpha band was apparent in the interictal EEG following the injection of 10 mg/kg lorcaserin although no individual time epoch reached statistical significance.

View Article: PubMed Central - PubMed

ABSTRACT

Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL11,939 and another selective 5-HT2A antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT2C agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT2C antagonist SB 242984. In summary, 5-HT2ARs and 5-HT2CRs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT2R subtypes might be potential novel anti-absence drugs.

No MeSH data available.