PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia

Michael G.R. Beyaert, Ritesh P. Daya, Bailey A. Dyck, Rodney L. Johnson, Ram K. Mishra

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Allosteric modulators are emerging as new therapeutics for the treatment of psychiatric illnesses, such as schizophrenia. Conventional antipsychotic drugs are typically dopamine D2 receptor antagonists that compete with endogenous dopamine at the orthosteric site, and block excessive dopamine neurotransmission in the brain. However, they are unable to treat all symptoms of schizophrenia and often cause adverse motor and metabolic side effects. The binding profile of allosteric modulators differs, as they interact with their receptor at a novel binding site and their activity is determined by physiological signaling. In collaboration, our laboratories have synthesized and evaluated over 185 compounds for their allosteric modulatory activity at the dopamine D2 receptor. Of these compounds, PAOPA is among the most potent allosteric modulators, and has been shown to be effective in treating the MK-801 induced preclinical animal model of schizophrenia. The objective of this study was to evaluate PAOPA's ability to prevent and reverse behavioral abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia. Amphetamine sensitized rats were given PAOPA during sensitization and following sensitization to determine whether PAOPA is able to prevent and reverse behavioral abnormalities. Furthermore, changes in post-mortem dopamine levels were measured by high performance liquid chromatography in various brain regions. The results presented demonstrate that PAOPA is able to prevent and reverse behavioral and biochemical abnormalities in an amphetamine-sensitized animal model of schizophrenia.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalEuropean Neuropsychopharmacology
Volume23
Issue number3
DOIs
StatePublished - Mar 2013

Bibliographical note

Funding Information:
Funding for this study was provided by NIH Grant NS20036; the NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Keywords

  • Allosteric regulation
  • Amphetamine
  • Animal models
  • Dopamine D2 receptor
  • PAOPA
  • Schizophrenia

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