Cocaine modulates both glutaminase gene expression and glutaminase activity in the brain of cocaine-sensitized mice

Abstract

Rationale: Glutaminase is considered the main glutamate (Glu)-producing enzyme. Two isoforms, liver (LGA)- and kidney (KGA)-type glutaminases, have been identified in neurons. The role of both enzymes in psychopharmacological responses to cocaine remains unknown.

Objectives: We examined both mRNA and protein expression of KGA and LGA in the brain of mice sensitized to cocaine. Additionally, total glutaminase activity was also measured.

Methods: Total glutaminase activity and mRNA and protein expression of KGA and LGA were measured on the dorsal striatum, prefrontal cortex, hippocampus and cerebellum of cocaine-sensitized mice.

Results: Cocaine-sensitized animals (20 mg/kg × 5 days, followed by 5 drug-free days) exhibited a decrease of total glutaminase activity in both the dorsal striatum and the prefrontal cortex. This was associated with an increase in KGA mRNA expression in both brain areas that was not observed when protein KGA levels were measured by western blot. LGA mRNA expression was increased as results of acute cocaine administration in sensitized animals, although protein levels were only enhanced in the prefrontal cortex of sensitized mice. These findings suggest that chronic cocaine administration modulates glutamate production through the regulation of glutaminase expression and activity. These actions are mainly observed in the prefrontal cortex-dorsal striatum circuit, the neuroanatomical target for the psychostimulant sensitization properties of cocaine.

Conclusions: The present results indicate that glutaminase enzymes (mainly KGA) are modulated by cocaine in both the prefrontal cortex and the dorsal striatum, as part of the neuroadaptions associated with behavioural sensitization to this drug of abuse.