An involvement of glutamatergic transmission in
schizophrenia has been postulated for several years. According to that view, hypofunction of
NMDA receptors and a compensatory increase in
glutamate release which overstimulates non-
NMDA receptors contributes to psychotic symptoms. Therefore, potential
antipsychotic drugs are searched for among compounds which block
AMPA receptors and inhibit
glutamate release. (R,S)-3,4-dicarboxyphenylglycine [(R,S)-3,4-DCPG] is a mixed antagonist of
AMPA receptors and agonist of an
autoreceptor, i.e.
metabotropic glutamate receptor 8. The aim of the study was to look for putative
antipsychotic properties of (R,S)-3,4-DCPG in the model of locomotor stimulation induced by
amphetamine or
phencyclidine in mice. Moreover, a risk of extrapyramidal side-effects induced by this compound was examined, as capability to induce
catalepsy in the bar test and to increase the
proenkephalin mRNA expression, measured autoradiographically in striatal slices by in situ hybridization. (R,S)-3,4-DCPG (80 mg/kg i.p.) decreased the
amphetamine (2.5 mg/kg s.c.)-but not
phencyclidine (3 mg/kg s.c.)-induced hyperactivity. That dose of (R,S)-3,4-DCPG did not decrease the spontaneous locomotor activity of mice. However, a dose of 100 mg/kg ip of that compound evoked
catalepsy and enhanced the
catalepsy and striatal
proenkephalin mRNA expression induced by
haloperidol (1-2 mg/kg i.p.). The study seems to suggest that (R,S)-3,4-DCPG may possess
antipsychotic properties at doses close to those evoking extrapyramidal side-effects which speaks for its rather typical than atypical
neuroleptic profile.