Antidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors

Abstract

Conventional antidepressant drugs elevate the availability of monoamine neurotransmitters. However, these pharmacological therapies have limited efficacy and a slow onset of action as main limitations. New glutamatergic drugs such as ketamine have shown promise as a rapid-acting antidepressant drugs although with adverse effects. The mechanism of action of ketamine is hypothesized to involve a dis-inhibition of cortical pyramidal neurons produced by an stimulation of AMPA receptors by glutamate. In this context, low-impact positive allosteric modulators of the AMPA receptors (a.k.a. ampakines) have been regarded as potential antidepressant drugs. Here, we have examined the behavioral, biochemical, and molecular effects of a low-impact ampakine, CX717. Our results show that CX717 has a rapid (30 min) but short-lasting (up to 24 h) antidepressant-like effect in the forced swim test. Intra-cortical infusion of CX717 increases the efflux of noradrenaline, dopamine, and serotonin, but not glutamate. However, systemic CX717 does not alter these neurotransmitters. CX717 also produced a rapid (up to 1 h) increase of brain-derived neurotrophic factor (BDNF) and a more sustained (up to 6 h) increase of p11. Overall, CX717 appears to possess a rapid but not sustained antidepressant action possibly caused by rapid increases of BDNF and p11.

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Acknowledgement

We thank RespireRX Pharmaceuticals for the generous gift of CX717.

Funding

This work was supported by the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (FIS Grant PI16/00217) that was co-funded by the European Regional Development Fund (‘A way to build Europe’). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged. The funding agencies had no role in the design and conduct of the study, collection, management, analyses, and interpretation of the data; and preparation, review, or approval of the manuscript and the decision to submit it for publication. MG-S and RP-A were recipients of contracts from the Sistema Nacional de Garantía Juvenil co-funded by the European Social Fund..

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Correspondence to Albert Adell.

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Gordillo-Salas, M., Pascual-Antón, R., Ren, J. et al. Antidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors. Mol Neurobiol 57, 3498–3507 (2020). https://doi.org/10.1007/s12035-020-01954-x

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Keywords

  • Ampakine
  • Antidepressant
  • Prefrontal cortex
  • BDNF
  • p11