Characterizing the cognitive, behavioural, and mechanistic actions of novel allosteric modulator PAOPA for the treatment of schizophrenia

Abstract

The pathophysiology, etiology, and treatment of schizophrenia remain elusive, but research is closing the gap. Schizophrenia globally affects less than 1% of the population and presents with positive, negative, and cognitive symptoms. As treatment for schizophrenia is not completely and meaningfully effective at treating all of the symptoms, without eliciting side effects, the current thesis aimed to evaluate a new drug candidate. PAOPA is a novel allosteric modulator that increases dopamine binding to the dopamine D2 receptor. It has previously shown positive findings in preventing and reversing behaviours proposed to model phenotypes of schizophrenia. However, it has not yet been tested to improve cognitive deficits in animal models, nor has its effects on other animals models been investigated. Lastly, its mechanism of action has not yet been comprehensively answered. In three separate studies, PAOPA was tested on ameliorating attentional deficits using the 5-choice serial reaction time task in an amphetamine model, deficits in novel objection recognition memory, sensorimotor gating, social interaction, and locomotor activity using a PCP model, and its effects on proteins regulating G protein-coupled receptors (GRK2 and arrestin-3), downstream signalling (ERK1 and ERK2), and synaptic vesicular control (synapsin II) were investigated. Although the sample sizes were too small to draw valid interpretations, the results suggested that PAOPA partially attenuated deficits in attention, novel object recognition memory, social interaction, sensorimotor gating, but not locomotor. Furthermore PAOPA increased the protein expression of GRK2, arrestin-3, ERK1 and 2, and synapsin IIa in the medial prefrontal cortex, striatum, and the nucleus accumbens. The results suggest that PAOPA influences the dopaminergic system in the striatum to change behaviour via receptor internalization and possibly downstream signalling. The present studies illuminate new insights, and point to future explorations for the potential development of PAOPA as a therapeutic for schizophrenia.