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.