As will be seen, dopamine is a major contributing
factor to the development of schizophrenia. Therefore, it is beneficial to
highlight specific gender differences in relation to dopaminergic systems, as
these systems are also affected by the remainder of the physiological factors.

One sex-specific characteristic that was found, was the role of catechol-O-methyl-transferase
(COMT), which metabolizes dopamine (Hill, 2015). Simply, a polymorphism in a
single nucleotide in the human COMT gene at codon 158 of Valine to Methionine
has been linked to reduced COMT enzymatic activity, and thus, schizophrenia (Witte
& Flöel, 2012; Hill, 2015). Interestingly, Risbrough, Ji, Hauger, &
Zhou (2014) developed the first “‘humanized'” COMT mouse model by inserting
COMT 158Met alleles into the mouse genome. Risbrough et al. (2014) tested the mice
who were Val/Val versus Met/Met, and found that male Val/Val mice were more
deficient in pre-pulse inhibition (PPI) and the opposite was true in female
mice. However, Met/Met female mice were more likely to experience fear
potentiated memory difficulties (Risbrough et al., 2014).

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In Hill’s (2015) studies with mice it was found that males expressed 17%
more COMT activity in the prefrontal cortex, but also showed higher levels of
COMT dysfunction in the frontal cortex. Likewise, Gogos et al., (1998) found a
similar increase in dopamine levels of male frontal cortexes. Male mice showed
increased levels of aggression, and their performance on medial prefrontal
cortex (MPFC)-dependent visuospatial learning tasks were deficient (Papaleo et
al., 2008; Gogos et al., 1998). It has also been established that cognitive
function was more impaired in male COMT knockout mice compared to females, with
stress playing a factor as a sex x genotype x environment interaction (Papaleo
et al., 2012). Whereas, female mice deficient in COMT were only shown to
express impaired emotional reactivity (Gogos et al., 1998).

Overall, mice lacking the dopamine transporter showed increased levels of
dopamine, impaired PPI, and hyperactivity (Hill, 2015). However, studies on the
role of elevated dopamine levels show that males are more vulnerable to changes
in dopaminergic signaling. Specifically, males showed a greater deficit in PPI,
and this may be because female models have been shown to have more efficient
recovery and packaging of extracellular dopamine. Though dependent on specific
types of mutation and cognitive tasks, males also tended to show a greater
detriment in cognitive phenotype (Hill, 2015).

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