Subchronic amphetamine decreases hyperactivity, anti-social behaviour and anhedonia in dopamine transporter knockout rats: role of prefrontal glutamate

Background and purpose: Hyperdopaminergia is a key feature of neuropsychiatric disorders including schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder and can be modeled using dopamine transporter knockout (DAT KO) rats. Previous studies have shown that acute amphetamine has a paradoxical calming effect in DAT KO rats, but the effects of repeated amphetamine treatment are unknown. Experimental approach: We studied the effect of subchronic amphetamine on hyperdopaminergia-related disease symptoms and underlying mechanisms using male and female DAT KO rats. We measured locomotor activity, anxiety-like behaviour, social behaviour, anhedonia and problem-solving behaviour at baseline and after 10 days of amphetamine treatment and assessed protein expression changes in the glutamate system in the prefrontal cortex. Key results: Both female and male DAT KO rats exhibited hyperlocomotion compared to control rats. Subchronic amphetamine treatment significantly dampened this effect in female, but not in male DAT KO rats. Additionally, amphetamine increased sociability in female, but not in male DAT KO rats. From a molecular point of view, we observed differences in the modulation of glutamatergic transmission between males and females mainly at the level of the infralimbic, but not prelimbic, prefrontal cortex, suggesting that the glutamatergic synapse may contribute to the behavioral response to amphetamine between the two sexes. Conclusion and implications: Subchronic amphetamine treatment decreased the hyperactivity, anxiety-like, anti-social and anhedonic phenotypes of female DAT KO rats, potentially by modulating glutamate transmission in the prefrontal cortex. These findings foster further research into the treatment of hyperdopaminergia-related disorders.