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

• Published in: Psychopharmacology Vol. 230; no. 1; pp. 57 - 67
• Main Authors: Konopaske, Glenn T., Bolo, Nicolas R., Basu, Alo C., Renshaw, Perry F., Coyle, Joseph T.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2013; Springer; Springer Nature B.V
• Subjects: Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - pharmacology; Astrocytes - drug effects; Astrocytes - metabolism; Biomedical and Life Sciences; Biomedicine; Brain; Chromatography, High Pressure Liquid; Complications and side effects; Dosage and administration; Drug therapy; GABA; gamma-Aminobutyric Acid - metabolism; Genetic aspects; Glucose - administration & dosage; Glucose - metabolism; Glutamic Acid - metabolism; Glutamine; Glutamine - metabolism; Haloperidol; Haloperidol - administration & dosage; Haloperidol - pharmacology; Homeostasis; Magnetic Resonance Spectroscopy; Male; Neurosciences; Original Investigation; Patient outcomes; Pharmacology/Toxicology; Physiological aspects; Prosencephalon - drug effects; Prosencephalon - metabolism; Psychiatry; Psychopharmacology; Rats; Rats, Sprague-Dawley; Rodents; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - physiopathology; Time Factors; United States; Brain; Neuron; C magnetic resonance spectroscopy; Rat; GABA; Haloperidol; Astrocyte; High-performance liquid chromatography; Glutamate; Glutamine
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-013-3136-3

Rationale 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. Objectives This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis. Methods We used ex vivo 13 C magnetic resonance spectroscopy along with high-performance liquid chromatography after [1- 13 C]glucose and [1,2- 13 C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months. Results Administration of haloperidol for 1 month produced no changes in 13 C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased 13 C labeling of glutamine by [1,2- 13 C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort. Conclusions 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.