5-HT2A receptor antagonists(Korea Research Institute of Chemical Technology)

Treating patients affected by schizophrenia (SZ) remains highly challenging for drug developers. While available antipsychotics mostly reduce positive symptoms, their effects on cognitive and social deficits as well as their underlying pathophysiology remain insufficient. Disinhibition in SZ patients' cortex is considered a key player in the genesis of these symptoms and would result from N-methyl-D-aspartate receptor (NMDAr) hypofunction on interneurons. Besides, electroencephalography-based biomarkers of these mechanisms including spontaneous and evoked gamma oscillations have been highlighted. These strongly depend on NMDAr function, associate with symptoms and therefore represent translational tools for drug development. However, reversing these circuit abnormalities is challenging for the field and finding drugs engaging them would constitute a major milestone. Here, we tested three different drugs whose features attract scientists for restoration of excitation/inhibition balance: cariprazine (D2/D3 receptor partial agonist and 5-HT_2A receptor antagonist), LY379268 (mGlur2/3 receptor agonist) and donepezil (acetylcholinesterase inhibitor). We investigated their effects on spontaneous oscillations and auditory steady-state responses (ASSR, measuring evoked gamma oscillations) in a rat model of SZ induced by MK-801, a selective NMDAr blocker. MK-801 increased locomotor activity, impaired spontaneous and evoked gamma oscillations and altered spontaneous oscillations in delta, alpha and beta frequencies of male Sprague Dawley rats. Remarkably, both cariprazine and LY379268 normalized spontaneous gamma oscillations. Moreover, cariprazine normalized alpha and beta waves and LY379268 selectively corrected delta activity. Interestingly, only cariprazine mitigated the ASSR deficit. These differential normalization profiles, including cariprazine's unique broad-spectrum signature, reveal distinct patterns of circuit engagement and provide a translational pharmaco-EEG framework for circuit-level target engagement in SZ drug development.

Osmoregulation is an essential process in all living organisms. For aquatic organisms, such as freshwater fishes whose natural environment is hypoosmotic, specialized cells, called ionocytes, are present in the skin during developmental stages and contribute to the maintenance of osmotic homeostasis. Such cells are known to proliferate in response to osmotic or ionic stress, but the molecular mechanism by which that process is regulated remains poorly characterized. In this study, using immunohistochemistry and confocal microscopy, we demonstrate that cutaneous ionocytes in developing zebrafish (Danio rerio) express serotonin 2A (5-HT2A) receptors by co-labelling with other known ionocyte markers, such as the Na+/K+-ATPase, Concanavalin A and Mitotracker. Furthermore, by quantifying ionocyte number through early stages of development, we implicate 5-HT2A receptors in initiating ionocyte proliferation. Exposure of zebrafish embryos and larvae to acidic pH, or exogenous 5-HT, increased the number of cutaneous ionocytes. The effects of both stimuli were abolished in the presence of the 5-HT2A receptor-specific antagonist, ketanserin. Moreover, activation of 5-HT2A receptors led to increased detection of ionocytes with phosphorylated extracellular signal-regulated kinase (ERK), a key regulator of cell division and differentiation linked with 5-HT2A. We used tetrabenazine, an inhibitor of vesicular monoamine transporter 2 (vmat2) and 5-HT storage, to deplete potential sources of 5-HT. Tetrabenazine treatment in fish exposed to acidic pH reduced ionocyte proliferation, implicating a source of 5-HT that uses vmat2 in the regulation of ionocyte populations. These results demonstrate the importance of a pathway initiated by 5-HT2A activation that regulates ionocyte proliferation in developing zebrafish exposed to environmental acidification.