Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain.

RATIONALE: The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-methyl-D: -aspartate receptors (NMDA-R). Several therapeutic strategies address NMDA-R function and the effects of antipsychotic agents on NMDA-R expression have been described. Within the second-generation antipsychotics, the partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract the behavioral effects of NMDA-R antagonists. OBJECTIVES: This study aims to investigate the effects of APZ on NMDA-R subunit expression and binding. METHODS: We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kilogram of body weight. Gene expression of the NMDA-R subunits NR1, NR2A, NR2B, NR2C, and NR2D, respectively, was assessed by semiquantitative radioactive in situ hybridization and in parallel receptor binding using (3)H-MK-801 receptor autoradiography. RESULTS: Increased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months), and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses of APZ, and the time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40-mg group and after 4 months in the 10-mg group. CONCLUSIONS: The effects of APZ converge in enhanced NMDA receptor expression and a shift of subunit composition towards adult-type receptors. Our results confirm the regulatory connections between dopaminergic, serotonergic, and glutamatergic neurotransmissions with relevance for cognitive and negative symptoms of schizophrenia.

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.