Differential expression of glutamate transporter genes after chronic oral treatment with aripiprazole in rats.
Glutamatergic neurotransmission is critically involved into the pathogenesis of schizophrenic psychosis, in particular regarding cognitive and negative symptoms. The reported molecular mechanisms include increased glutamate transporter expression and antipsychotic agents such as clozapine were found able to suppress the expression of these genes. So far, the effects of the partial dopaminergic and serotonergic agonist aripiprazole on glutamatergic neurotransmission were never investigated. In a rat animal model of long-term antipsychotic treatment, we analyzed the expression of glutamate transporter genes after treatment with aripiprazole. Groups of 6 male Sprague-Dawley rats were treated for 4 weeks or 4 months with daily oral doses of 10 or 40mg aripiprazole per kg. Using semi-quantitative in situ-hybridization, we assessed the expression of pre- and post-synaptic glutamate transporter genes. Compared to control animals, differential expression levels were found in several cortical and hippocampal regions. The astroglial excitatory amino acid transporter genes EAAT1 and EAAT2 as well as the neuronal transporter EAAT3 were suppressed, while the presynaptic vesicular glutamate transporter vGluT1 was transiently induced in hippocampal subregions and EAAT4 was transiently suppressed in frontocortical areas. These transcriptional effects exerted by aripiprazole may counteract a glutamatergic deficit state and strengthen the neurotransmission of glutamate with positive consequences on cognitive and negative symptoms of schizophrenia.
Segnitz
Nina
N
University of Heidelberg, Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Mannheim, Germany.
Schmitt
Andrea
A
Gebicke-Härter
Peter J
PJ
Zink
Mathias
M
D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers / Q000187:drug effects; D017403:In Situ Hybridization; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D027322:Amino Acid Transport System X-AG; D014150:Antipsychotic Agents; D005819:Genetic Markers; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole