Region-specific effects of repeated ketamine administration on the presynaptic GABAergic neurochemistry in rat brain.
A growing body of evidence indicates that clinical use of ketamine as a promising antidepressant can be accompanied by psychotic-like side effects. Although, the generation of such effects is thought to be attributed to dysfunction of prefrontal GABAergic interneurons, the mechanism underlying ketamine's propsychotic-like action is not fully understood. Due to wide spectrum of behavioral abnormalities, it is hypothesized that ketamine action is not limited to only cortical GABA metabolism but may also involve alterations in other functional brain areas. To test it, we treated rats with ketamine (30 mg/kg, i.p.) for 5 days, and next we analyzed GABA metabolizing enzymes in cortex, cerebellum, hippocampus and striatum. Our results demonstrated that diminished GAD67 expression in cortex, cerebellum (by ∼60%) and in hippocampus (by ∼40%) correlated with lowered protein level in these areas. The expression of GAD65 isoform decreased by ∼45% in striatum, but pronounced increase by ∼90% was observed in hippocampus. Consecutively, reduction in glutamate decarboxylase activity and GABA concentration were detected in cortex, cerebellum and striatum, but not in hippocampus. Ketamine administration decreased GABA transaminase protein in cortex and striatum (by ∼50% and 30%, respectively), which was reflected in diminished activity of the enzyme. Also, a significant drop in succinic semialdehyde dehydrogenase activity in cortex, cerebellum and striatum was present. These data suggest a reduced utilization of GABA for energetic purposes. In addition, we observed synaptic GABA release to be reduced by ∼30% from striatal terminals. It correlated with lowered KCl-induced Ca(2+) influx and decreased amount of L-type voltage-dependent calcium channel. Our results indicate that unique changes in GABA metabolism triggered by chronic ketamine treatment in functionally distinct brain regions may be involved in propsychotic-like effects of this drug.
Department of Molecular Neurochemistry, Medical University of Lodz, Mazowiecka 6/8 Str., 92215 Lodz, Poland. Electronic address: tomasz.boczek@umed.lodz.pl.
Tomasz
T
Boczek
Department of Molecular Neurochemistry, Medical University of Lodz, Mazowiecka 6/8 Str., 92215 Lodz, Poland.
Malwina
M
Lisek
Department of Molecular Neurochemistry, Medical University of Lodz, Mazowiecka 6/8 Str., 92215 Lodz, Poland.
Bozena
B
Ferenc
Department of Molecular Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8 Str., 92215 Lodz, Poland.
Magdalena
M
Wiktorska
Ss. Cyril and Methodius University of Skopje, Faculty of Natural Sciences and Mathematics, Arhimedova 3 Str., 1000 Skopje, Republic of Macedonia.
Ivana
I
Ivchevska
Department of Molecular Neurochemistry, Medical University of Lodz, Mazowiecka 6/8 Str., 92215 Lodz, Poland.
Ludmila
L
Zylinska
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D020746:Calcium Channels, L-Type / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017661:Receptors, Presynaptic / Q000187:drug effects*; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D018691:Excitatory Amino Acid Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D017661:Receptors, Presynaptic; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D013385:Succinate Dehydrogenase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
Calcium; GABA metabolism; GABA transport; Ketamine; N-methyl-d-aspartate receptor