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

Abstract

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.

Introduction

The dopaminergic system contributes to the pathophysiology of schizophrenia. However, the action of a single neurotransmitter system does not explain all the clinical features of this disease. Thus, studies suggest that schizophrenia results from an imbalance among several interacting neurotransmitter systems including the dopaminergic, serotonergic, glutamatergic, cholinergic, and GABAergic systems (as reviewed in Carlsson et al., 2001). Therefore, the best candidate for treatment of schizophrenia will be a drug that is able to modulate several neurotransmitter systems instead of acting only on the dopaminergic system.

A large amount of evidence gathered over the past two decades suggests that targeting the neurotensin (NT) system may provide a novel and promising treatment for schizophrenia (Breslin et al., 1994, Garver et al., 1991, Sharma et al., 1997). This is because in the central nervous system, NT acts as a neurotransmitter or a neuromodulator affecting several neurotransmitter systems implicated in schizophrenia including dopaminergic, serotonergic, GABAergic, glutamatergic, and cholinergic (Kinkead et al., 1999). Biochemical studies have shown that antipsychotic drug treatments increase NT transmission, and centrally administrated NT produces biochemical and behavioral effects similar to those observed following administration of antipsychotic drugs (Binder et al., 2001, Kinkead et al., 1999, Nemeroff, 1980).

NT mediates its effects through its receptors: the high affinity NT receptor (NTS1) (Vita et al., 1993), the low affinity NT receptor (NTS2) (Mazella et al., 1996), and NTS3 (Mazella et al., 1998). Both NTS1 and NTS 2 mediate several of the central and peripheral effects of NT and play a major role in the modulation of neurotransmitter systems (Pettibone et al., 2002, Antonelli et al., 2007, Leonetti et al., 2004; Boules et al., 2010). However, very little is known about the physiological role of NTS3.

Several studies show that there are differences in behavior and response to drugs between both NTS1^−/− and NTS2^−/− mice compared to WT mice: 1) NTS1^−/− mice have hyperphagia and abnormal weight gain (Kim et al., 2008); 2) NTS2^−/− mice have less freezing response as compared to that for WT mice in a fear-conditioning test (Yamauchi et al., 2007); 3) PD149163, a NT receptor agonist, significantly facilitates prepulse inhibition (PPI) and decreases the acoustic startle response in WT but not NT1 KO mice (Feifel et al., 2010); 4) NT peptide knockout mice (NT^−/−) exhibit reduced PPI and no amphetamine-induced disrupted PPI as compared with wide type mice (Kinkead et al., 2005); and 5) Peripheral administration of NT receptor agonists (NT-2 and NT69L) reverses apomorphine-induced climbing in wild type but not in NTS1^−/− mice (Mechanic et al., 2009). These data indicate that NT receptors play an important role in animal models related to schizophrenia. The present study was designed to investigate the changes of amino acid levels in the striatum in NTS1 and NTS2-null mice in a DA-based animal model. The results provide support for the idea that both NTS1^−/− and NTS2^−/− mice provide animal models for studies related to schizophrenia.