1. Academic Validation
  2. Lumateperone-mediated effects on prefrontal glutamatergic receptor-mediated neurotransmission: A dopamine D1 receptor dependent mechanism

Lumateperone-mediated effects on prefrontal glutamatergic receptor-mediated neurotransmission: A dopamine D1 receptor dependent mechanism

  • Eur Neuropsychopharmacol. 2022 Sep;62:22-35. doi: 10.1016/j.euroneuro.2022.06.009.
J Titulaer 1 O Radhe 2 K Danielsson 3 S Dutheil 4 M M Marcus 5 K Jardemark 5 T H Svensson 5 G L Snyder 4 M Ericson 3 R E Davis 4 Å Konradsson-Geuken 6
Affiliations

Affiliations

  • 1 Section of Neuropharmacology and Addiction Research, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. Electronic address: joep.titulaer@farmbio.uu.se.
  • 2 Section of Neuropharmacology and Addiction Research, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
  • 3 Addiction Biology Unit, Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
  • 4 Intra-Cellular Therapies, Inc., New York, NY, United States.
  • 5 Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
  • 6 Section of Neuropharmacology and Addiction Research, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Abstract

Lumateperone is a novel drug approved for the treatment of schizophrenia in adults and depressive episodes associated with bipolar depression in adults, as monotherapy and as adjunctive therapy with lithium or valproate treatment in the United States. Lumateperone simultaneously modulates key neurotransmitters, such as serotonin, dopamine, and glutamate, implicated in serious mental illness. In patients with schizophrenia, lumateperone was shown to improve positive symptoms along with negative and depressive symptoms, while also enhancing prosocial behavior. Moreover, in patients with bipolar I or II disorder, lumateperone improved depressive symptoms as well. To further understand the mechanisms related to lumateperone's clinical response, the aim of this study was to investigate the effect of lumateperone on dopaminergic- and glutamatergic signaling in the rat medial prefrontal cortex (mPFC). We used the conditioned avoidance response (CAR) test to determine the antipsychotic-like effect of lumateperone, electrophysiology in vitro to study lumateperone's effects on NMDA- and AMPA-induced currents in the mPFC, and the neurochemical techniques microdialysis and amperometry to measure dopamine- and glutamate release in the rat mPFC. Our results demonstrate that lumateperone; i) significantly suppressed CAR in rats, indicating an antipsychotic-like effect, ii) facilitated NMDA and AMPA receptor-mediated currents in the mPFC, in a dopamine D1-dependent manner, and iii) significantly increased dopamine and glutamate release in the rat mPFC. To the extent that these findings can be translated to humans, the ability of lumateperone to activate these pathways may contribute to its demonstrated effectiveness in safely improving symptoms related to neuropsychiatric disorder including mood alterations.

Keywords

Antipsychotic drug; Dopamine; Glutamate; Lumateperone; Medial prefrontal cortex; Schizophrenia.

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