Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model

Schizophrenia is characterized by positive, negative, and cognitive symptoms. However, current D2-based antipsychotic drugs only address primarily positive symptoms. Limbic hippocampus hyperexcitability is a key pathological state of schizophrenia, representing an ideal therapeutic target. Evenamide is a selective voltage-gated sodium channel blocker that reduces neuronal hyperexcitability. We examined the effect of acute evenamide treatment on the hyperdopaminergic state, hippocampal hyperexcitability, social deficits, and recognition memory in the methylazoxymethanol acetate (MAM) neurodevelopmental model. Male and female Sprague-Dawley offspring from dams treated with saline or MAM on gestational day 17 were tested as adults (postnatal day >65). Electrophysiological recordings were made in the ventral tegmental area (VTA) and ventral hippocampus (vHipp) and social approach and novel object recognition were tested. Evenamide (3 mg/kg i.p.) normalized the number of spontaneously active DA neurons in the VTA of female and male MAM rats and reduced pyramidal neuron hyperactivity in the vHipp. The hyperdopaminergic state in the VTA of female and male MAM rats was also rescued by local evenamide injection in the vHipp (1 µM). Systemic evenamide also reversed the recognition memory impairment of female and male MAM rats. For social deficits, only male MAM rats exhibit a reduced social sniffing time that was normalized by evenamide. These findings suggest that evenamide's efficacy in downregulating the hyperdopaminergic state, social deficits, and recognition memory impairment may result from its ability to attenuate vHipp hyperexcitability. Therefore, evenamide could offer a novel therapeutic strategy that is capable of addressing positive, cognitive, and negative symptoms of schizophrenia.