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

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.

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Some typical 5-HT 2C R agonists dose-dependently suppressed absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established polygenic rat model of absence epilepsy and non-convulsive seizures; these effects were prevented when administering a selective 5-HT 2 C R antagonist, indicating the potential of selective 5-HT 2C R agonists as novel anti-absence drugs (Venzi et al, 2016). Experiments on Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) rats, another polygenic rat model of absence epilepsy, have found that mCPP decreased spike-wave discharges (SWDs) cumulative duration via the activation of 5-HT 2C Rs (Jakus et al, 2003).…”

“…As both epilepsy and monoamine-based neuropsychiatric disorders are complex diseases that imply changes in multiple neurotransmitters and both neuronal and glial cells activity, a comprehensive understanding of the underlying mechanisms is still in its infancy. Nevertheless, this evidence of dual link between these two disorders suggest that drugs targeting monoamines may be useful for both epilepsy and its neuropsychiatric comorbidities (Guiard and Di Giovanni, 2015; Venzi et al, 2016). …”

Modulating the Serotonin Receptor Spectrum of Pulicatin Natural Products

“…19,20 The antiseizure activity of pulicatin B ( 1 ) was tested in mice at the NIH/NINDS Epilepsy Therapy Screening program contract site at the University of Utah. Four mice each were used for initial screening in the maximal electroshock seizure (MES) 21,22 and 6 Hz psychomotor seizure tests 23 (Table 5).…”

“…The electrical stimulus in the MES test (50 mA, 60 Hz, 0.2 sec) was delivered via corneal electrodes by an apparatus similar to that originally described by Woodbury and Davenport. 19 Abolition of the hind leg tonic extensor component is taken as the endpoint for this test. Efficacy on four mice was compared by evaluating the following i.p.…”

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

“…5-HT2CR are expressed in the amygdala, and fMRI data have demonstrated that 5-HT 2C R agonists lead to its neuronal activation (Hackler et al 2007). Other therapeutic indications relate to obesity and possibly epilepsy Brennan et al 1997;Heisler et al 1998;2007a; as observed in the first series of receptor transgenic mice and later with 5-HT2CR selective ligands (Venzi et al 2016;Bagdy et al 2007;Jakus et al 2003;Isaac 2005). It is still a challenge to synthesise 5-HT 2CR selective agonists, devoid of significant interactions with the other 5-HT2 receptor subtypes, since 5-HT2B receptor activation results in detrimental cardiac effects such as valvulopathies (see Fitzgerald et al 2000;Roth 2007), whereas 5-HT2AR activation leads to hallucinations (Nichols 2004).…”