MK-212

Epilepsy is a common neurological condition that affects over 65 million people worldwide. Despite an increasing number of anti-seizure medications being made available, many patients do not find seizure freedom with medication. The leading cause of death in this refractory population is sudden unexpected death in epilepsy (SUDEP). Both human and animal research has implicated serotonin (5-HT) in modulating seizure proclivity, severity, and mortality. More recently, evidence has pointed to the 5-HT_2C receptor as a salient target for investigating the mechanisms of seizure facilitation and mortality. Various seizures models have been used previously to assess the role of the 5-HT_2C receptor in seizure expression and morphology. However, limbic kindling models have been underutilized in this endeavor. We used the selective 5-HT_2C receptor agonist MK-212 to examine the effect of 5-HT_2C receptor activation in amygdala kindled mice. C57BL/6J mice were instrumented with an EEG/EMG headmount and a bipolar electrode in the basolateral amygdala (BLA). The animals then received vehicle or MK-212 (10, 30 mg/kg) prior to seizure induction. 12.5% of WT animals that received 10 mg/kg MK-212 experienced seizure-induced respiratory arrest and died following seizure induction. When the dose was raised to 30 mg/kg, 100% of the animals succumbed following a seizure. These fatal seizures persisted when the same doses of MK-212 were administered to mice lacking the 5-HT_2C receptor. This suggests that a non-5-HT_2C mediated effect of MK-212 facilitates seizure-induced death in a dose-dependent manner. While amygdala kindling is not a model that is traditionally associated with seizure-induced death, these results suggest that there are circuits that, when recruited, will cause death following kindled seizures. Uncovering these circuits will both deepen our understanding of the amygdala kindling model and provide a new technique for researchers to test novel therapeutic interventions to lessen SUDEP risk.

The effects of previous social experiences on social behavior have been demonstrated across species both in cooperative and competitive contexts. In dominance-subordinate hierarchies, differences across social ranks have been observed in many different mechanisms. Dominance hierarchies interfere in defensive behavior, where subordinate animals present a greater defensive behavior, regarding potential threats ("anxiety-like behavior"), than dominant animals. The serotonergic system plays a key role in regulating and mediating threat responses, including 5-HT2 receptors in the types of proximal threat responses modulated by the stress of social defeat. We separated 148 adult zebrafish in pairs and allowed them to interact for five days; after that, the dominant-subordinate rank was determined, and animals were treated with a 5-HT_2C receptor agonist (MK-212) or antagonist (RS-102221) before being observed in the novel tank test. While MK-212 increased bottom-dwelling, erratic swimming, and freezing across all statuses, RS-102221 decreased these variables in dominants but increased them in subordinates. Moreover, the effects of MK-212 were larger in subordinates than in controls or dominants, suggesting a sensitization of the 5-HT_2C receptor.