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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 5-HT2A/CRs modulation on SWDs peak frequency. (A) Representative spike and wave discharge (SWD) (red, top) and corresponding wavelet power spectrum on a time-frequency representation (bottom). The peak frequency of the SWD was identified by extracting the instantaneous frequency of the power maximum in the range 5–14 Hz at each time point of the SWD (magenta line in time-frequency plot) and subsequently calculating its mean. (B) Changes (mean ± SEM) in SWD peak frequency induced by administration of 5-HT2AR and 5-HT2CR agonists and antagonists (bottom row) isolated or in combination with another drug (doses in mg/kg are reported at the bottom of the graph). Asterisks indicate p < 0.05 (independent samples t-test for drug vs vehicle).
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fig3: Effect 5-HT2A/CRs modulation on SWDs peak frequency. (A) Representative spike and wave discharge (SWD) (red, top) and corresponding wavelet power spectrum on a time-frequency representation (bottom). The peak frequency of the SWD was identified by extracting the instantaneous frequency of the power maximum in the range 5–14 Hz at each time point of the SWD (magenta line in time-frequency plot) and subsequently calculating its mean. (B) Changes (mean ± SEM) in SWD peak frequency induced by administration of 5-HT2AR and 5-HT2CR agonists and antagonists (bottom row) isolated or in combination with another drug (doses in mg/kg are reported at the bottom of the graph). Asterisks indicate p < 0.05 (independent samples t-test for drug vs vehicle).

Mentions: The behavioral and EEG features of ASs recorded in vehicle-treated, freely moving GAERS were similar to those previously reported for this experimental model under similar experimental conditions (Cope et al., 2009, Danober et al., 1998). These included behavioral arrest, with occasional head and vibrissae twitching, and SWDs of 16.1 ± 14.3 s duration and 6.90 ± 0.72 Hz peak frequency (n = 8914 seizures, mean ± standard deviation) (see Fig. 3A).


Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures
Effect 5-HT2A/CRs modulation on SWDs peak frequency. (A) Representative spike and wave discharge (SWD) (red, top) and corresponding wavelet power spectrum on a time-frequency representation (bottom). The peak frequency of the SWD was identified by extracting the instantaneous frequency of the power maximum in the range 5–14 Hz at each time point of the SWD (magenta line in time-frequency plot) and subsequently calculating its mean. (B) Changes (mean ± SEM) in SWD peak frequency induced by administration of 5-HT2AR and 5-HT2CR agonists and antagonists (bottom row) isolated or in combination with another drug (doses in mg/kg are reported at the bottom of the graph). Asterisks indicate p < 0.05 (independent samples t-test for drug vs vehicle).
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4920646&req=5

fig3: Effect 5-HT2A/CRs modulation on SWDs peak frequency. (A) Representative spike and wave discharge (SWD) (red, top) and corresponding wavelet power spectrum on a time-frequency representation (bottom). The peak frequency of the SWD was identified by extracting the instantaneous frequency of the power maximum in the range 5–14 Hz at each time point of the SWD (magenta line in time-frequency plot) and subsequently calculating its mean. (B) Changes (mean ± SEM) in SWD peak frequency induced by administration of 5-HT2AR and 5-HT2CR agonists and antagonists (bottom row) isolated or in combination with another drug (doses in mg/kg are reported at the bottom of the graph). Asterisks indicate p < 0.05 (independent samples t-test for drug vs vehicle).
Mentions: The behavioral and EEG features of ASs recorded in vehicle-treated, freely moving GAERS were similar to those previously reported for this experimental model under similar experimental conditions (Cope et al., 2009, Danober et al., 1998). These included behavioral arrest, with occasional head and vibrissae twitching, and SWDs of 16.1 ± 14.3 s duration and 6.90 ± 0.72 Hz peak frequency (n = 8914 seizures, mean ± standard deviation) (see Fig. 3A).

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.