Translating the MAM model of psychosis to humans

Abstract

Elevated dopamine function and alterations in medial temporal lobe (MTL) structure and function are two of the most robust findings in schizophrenia, but how interactions between these abnormalities underlie the onset of psychosis is unclear. The methylazoxymethanol acetate (MAM) rodent model proposes that psychosis develops as a result of a perturbation of MTL function, leading to elevated striatal dopamine dysfunction. Here, we review several recent neuroimaging studies that examine components of the putative model in humans with an ultra high risk (UHR) of the psychosis. While data from these studies are broadly consistent with the MAM model, caution is required when comparing data across animal and human studies.

Keywords: animal research; neurobiology; neuroimaging; prodrome; psychosis; schizophrenia.

Figure 1

Altered relationship between cortical activation and subcortical dopamine function in subjects at Ultra High Risk of Psychosis (UHR). (A) Functional activation in the left inferior frontal gyrus (IFG) during verbal fluency is positively correlated with presynaptic dopaminergic activity in the associative striatum [108]. (B) Functional activation in the right IFG during working memory is positively correlated in healthy controls but negatively correlated in UHR subjects [107]. (C) Functional activation in the medial temporal lobe (MTL) during verbal encoding is positively correlated with subcortical dopamine levels in UHR subjects but not in healthy controls [105]. (D) MTL activation during verbal recognition was negatively correlated with dopamine levels in the healthy control group but not in the UHR group [105]. (E) Abnormal interaction between functional activation in right hippocampus and subcortical dopamine function during the processing of reward salience [106]. Ki = ¹⁸F-fluorodopa influx constants. All figures adapted with permission from the author’s original work.