Effect of amphetamine on extracellular concentrations of amino acids in striatum in neurotensin subtype 1 and 2 receptor null mice: A possible interaction between neurotensin receptors and amino acid systems for study of schizophrenia

Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors: NTS1 and NTS2. The present study was done to determine the roles of NTS1 and NTS2 on amino acid release in striatum with the use of NTS1 or NTS2 knockout (^-/-) mice given d-amphetamine. Both NTS1^-/- and NTS2^-/- mice had lower extracellular concentrations of d-serine in striatum than did wild type (WT) mice. NTS2^-/- but not NTS1^-/- mice also had significantly lower basal concentrations of glutamate in striatum as compared to that for WT mice. Systemic administration of d-amphetamine (4 mg/kg, ip) increased glutamate release by 500% in WT mice, as compared to 300% in NTS2^-/- mice, and 250% in NTS1^-/- mice. Additionally, d-amphetamine injection caused a 4-fold increase in GABA release in both WT and NTS2^-/- mice, but only a 2-fold increase in NTS1^-/- mice. Therefore, NTS1 and NTS2 modulate basal release of d-serine and glutamate, and also d-amphetamine-induced GABA and glutamate release in striatum. These results provide further support for the involvement of NT receptors in the pathogenesis of schizophrenia and provide a better understanding of the imbalance of amino acid systems through investigation of a DA-based animal model.