Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile

Abstract

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

“…Similarly, chlorpromazine, a first-generation antipsychotic, was effective in preventing the excitatory action of ketamine on the EEG bands of the hippocampus, with an even more pronounced effect after the addition of alpha-lipoic acid [ 130 ]. These findings were supported by a recent study, in which haloperidol, clozapine, and risperidone effectively prevented the PCP-induced desynchronization of the PFC in rats [ 127 ]. In the same study, the effect of a novel compound EGIS-11150, an inhibitor of adrenergic alpha1 and alpha2c, and serotonergic 5-HT 2A R and 5-HT 7 R receptors, were evaluated after both PCP and ketamine administrations [ 127 ].…”

“…A replicated feature found in the included preclinical studies was the detrimental consequence of NMDAR antagonists, such as PCP, MK-801, and ketamine, on prefrontal and hippocampal activity [ 40 , 127 , 145 ]. Given the key role in regulating high-level cognitive functions, including learning, behavioral flexibility, novelty processing, and memory, alterations in the hippocampus–PFC pathway have a remarkable translational value [ 127 ].…”

“…A replicated feature found in the included preclinical studies was the detrimental consequence of NMDAR antagonists, such as PCP, MK-801, and ketamine, on prefrontal and hippocampal activity [ 40 , 127 , 145 ]. Given the key role in regulating high-level cognitive functions, including learning, behavioral flexibility, novelty processing, and memory, alterations in the hippocampus–PFC pathway have a remarkable translational value [ 127 ]. In this framework, dysconnectivity within networks comprising both hippocampus and PFC was detected in patients affected by schizophrenia and proposed as a possible driver of impairments in the working memory domain [ 152 , 153 ].…”

“…PCP was found to induce different patterns of brain activity depending on its levels, with high doses globally impairing functional connectivity and low doses affecting mainly the hippocampal and frontal regions [ 123 ]. The alteration in the hippocampal-PFC pathway is particularly relevant to the physiopathology of schizophrenia, as this pathway is involved in the regulation of learning, behavioral flexibility, novelty processing, and memory and has been found to be impaired in patients with schizophrenia [ 124 , 125 , 126 , 127 ].…”

“…In the same study, the effect of a novel compound EGIS-11150, an inhibitor of adrenergic alpha1 and alpha2c, and serotonergic 5-HT 2A R and 5-HT 7 R receptors, were evaluated after both PCP and ketamine administrations [ 127 ]. EGIS-11150 not only showed to fully tackle the EEG modifications induced by ketamine and PCP but also to increase the hippocampus-PFC coherence and reverse the inhibition of long-term potentiation (LTP) induced by stressors more than clozapine and haloperidol [ 127 ].…”