Investigating PAOPA, a new potential antipsychotic for the treatment of schizophrenia: an in vivo microdialysis study

Schizophrenia is a mental disorder that affects approximately 1% of the global population. The disorder is largely characterized into three main symptom groups: positive, negative, and cognitive. Conventional antipsychotic drugs (APDs) act as dopamine D2 receptor antagonists that compete with endogenous dopamine at the orthosteric binding site, thereby attempting to attenuate psychotic symptoms marked by striatal hyperdopaminergic signalling. Unfortunately, APDs are associated with adverse motor and metabolic side effects. In order to circumvent the challenges posed by the evolutionarily conserved nature of orthosteric sites when creating highly selective D2 receptor ligands, selective positive allosteric modulators (PAMs) are used. PAOPA, in addition to attenuating behavioural abnormalities in preclinical amphetamine-induced animal models of schizophrenia, has proven to be the most potent positive allosteric modulator of the dopamine D2 receptor. However, the mechanism through which PAOPA mediates its effects remains unclear. Three groups (n=14, n=3-5/group) of male Sprague Dawley rats received subcutaneous injections of d-amphetamine (1mg/kg) following a 0.9% saline (1mL/kg) or PAOPA (1mg/kg) pre-treatment. Following treatment, in vivo striatal dialysate samples were collected using microdialysis to assess whether the behavioural changes measured in the locomotor test were associated with changes in dopamine levels. Interestingly, PAOPA pre-treatment attenuated the amphetamine-induced locomotor hyperactivity, confirming previous results which suggest D2 receptor internalization. PAOPA also reduced striatal dopamine dialysate levels overall, but not at the 20 or 40 minute interval. PAOPA treatment alone had no effect. This study presents further avenues of exploration for the potential development of PAOPA as a novel APD.

Written by Omar Shawaf

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