Differential effects of long-term treatment with clozapine or haloperidol on GABA transporter expression.
BACKGROUND
Post-mortem studies with brain samples of schizophrenic patients led revealed altered GABA-ergic markers like reduced expression of the GABA transporter GAT-1. Whether this effect is due to the pathophysiology of schizophrenia or to antipsychotic treatment has not been investigated. We therefore established an animal trial of long-term antipsychotic treatment to address this question.


METHODS
A total of 33 adult male rats were investigated in three cohorts of 11 animals. One group received clozapine (45 mg/kg/ day), another group haloperidol (1.5 mg/kg/day), and the third one pH-adapted water over a period of 6 months. In situ hybridization with cRNA probes specific for GABA transporters VGAT, GAT-1 and GAT-3 were performed in comparison to control animals.


RESULTS
While GAT-1 was upregulated, VGAT expression declined in cortical and limbic brain regions, whereby haloperidol showed a greater effect than clozapine. GAT-3 expression was suppressed in parietal and temporal cortex.


CONCLUSIONS
We thus conclude that long-term antipsychotic treatment alters GABA transporter expression in rat. The upregulation of GAT-1 contrasts with the post-mortem finding of reduced GAT-1 expression in schizophrenic patients. Our results facilitate the distinction between disease dependent changes of GABAergic markers and medication effects.
Central Institute of Mental Health, Department of Psychiatry, Mannheim, Germany. zink@kv.zi-mannheim.de
M
M
Zink
A
A
Schmitt
B
B
May
B
B
Müller
D F
DF
Braus
F A
FA
Henn
D026905:Amino Acid Transport Systems / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D050485:GABA Plasma Membrane Transport Proteins; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D018075:RNA, Complementary / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D033921:Vesicular Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000008:administration & dosage
D026905:Amino Acid Transport Systems; D014150:Antipsychotic Agents; D050485:GABA Plasma Membrane Transport Proteins; D026901:Membrane Transport Proteins; D018075:RNA, Complementary; C118623:Slc32a1 protein, rat; C493415:Slc6a1 protein, rat; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D033921:Vesicular Transport Proteins; D014867:Water; D003024:Clozapine; D006220:Haloperidol