Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain

Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al., Biol Psych 63:759-765, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis. This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis. We used ex vivo C-13 magnetic resonance spectroscopy along with high-performance liquid chromatography after [1-C-13]glucose and [1,2-C-13]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months. Administration of haloperidol for 1 month produced no changes in C-13 labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased C-13 labeling of glutamine by [1,2-C-13]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort. Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment.