The role of serotonin 2C receptors in comorbid neuropsychiatric symptoms in absence epilepsy

Abstract

Aim / Introduction: The aim of this study was to evaluate the role of lorcaserin, an FDA-approved drug for obesity, in neuromodulation of 5-HT2C receptors and its effects on the neuropsychiatric comorbidities of absence epilepsy – depression & anxiety in Generalised Absence Epilepsy Rats from Strasbourg (GAERS) and Non-Epileptic Control (NEC) rats. It was hypothesised that through the potentiation of the 5-HT2C receptor signalling, it would be possible to positively modulate these comorbidities; thereby reducing symptoms of depression and anxiety as they are related to epilepsy. GAERS rats were selected as they are genetically modified rat models that exhibit electrographic and behavioural similarity to human absence seizures.

Human absence epilepsy is typically associated with a non-convulsive epileptic seizure whereby the patient experiences a brief episode of impairment of consciousness with an electroencephalogram classically showing a 2.5-4Hz spike-and-wave discharge (SWD) (Engel & Pedley, 2008). Seizures tend to start in the first decade of life, with ictal activity peaking at 6 to 7 years of age. At times, a child can experience up to 200 seizures a day, each lasting approximately 10 seconds (International League Against Epilepsy, 1989). The psychiatric comorbidities of absence seizures include depression, anxiety and attention deficits – subsequently affecting schooling, employment and possibly inducing social withdrawal. Method: A total of 31 GAERS and 31 NEC rats were injected with either saline (n=15) or lorcaserin solution 3mg/kg (n=16) prior to undergoing behavioural testing, namely – the Hole Board Test, the Elevated Plus Maze Test and the Forced Swimming Test. The rats' behaviour was categorised using predefined behaviours which were recorded and analysed offline using the programme – Observer 2.0 by Noldus, thus allowing for a quantifiable comparative statistical analysis. This was performed using 2-way ANOVA so as to ascertain any significance between strain of rat or treatment, with Tukey’s post hoc analysis used if any interaction between these variables occurred.

Results: When administered at 3mg/kg, lorcaserin, a 5-HT2C receptor agonist, appeared to have an anxiogenic and depressogenic effect on both controls and GAERS rats– as exhibited by the decreased head dip to edge sniff ratio and increased body grooming with lorcaserin in Hole Board testing. Notably, both NEC & GAERS rats spent more time in the closed arm when treated with lorcaserin in Elevated Plus Maze testing, a behaviour that is typical of anxious rats. Furthermore, lorcaserin appears to induce hypoactivity as exhibited by the decreased walking time and increased immobility in Hole Board testing. A longer immobility time in the Forced Swimming Test for rats treated with lorcaserin irrespective of rat strain is confirmatory of its hypolocomotive effect.

Conclusion: Across the three methods of behavioural testing, this study repeatedly illustrated the anxiogenic, depressogenic and hypoactive nature of lorcaserin at the predetermined 3mg/kg concentration, across both NEC & GAERS rat strains. The negation of this hypothesis offers a basis for further work with the possibility of exploring the effects of lorcaserin at different concentrations, assessing the electrophysiological activity itself in relation to the psychiatric sequelae and the use of other selective 5-HT2C agonists so as to establish their role of psychiatric symptom modulation in absence epilepsy.