Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of
schizophrenia. Previous behavioral studies have indicated that metabotropic
glutamate (mGlu) receptors may be useful targets for the treatment of
psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential
antipsychotic effects in behavioral models of
schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and
neurodegenerative disorders. However, despite encouraging data in animal models, most
ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic
acid (
ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of
psychosis or
hallucinations. The results of the present study show that
ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased
amphetamine-induced hyperlocomotion in rats. Furthermore,
ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that
ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of
schizophrenia.