Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NT69L is a neurotensin receptor agonist with antipsychotic-like activity. NT69L blocks apomorphine-induced climbing in rats with no effect on stereotypic behavior, attenuates d-amphetamine-induced hyperactivity, and blocks pharmacologically induced disruption of prepulse inhibition (PPI) of the startle response. Repeated administration of NT69L results in tolerance to some, but not to all of its effects. Because schizophrenic patients require long-term treatment, chronic (21-day) administration of NT69L was tested in PPI with comparisons to chronic haloperidol and clozapine treatment. Sprague-Dawley rats received acute or 21 daily, subcutaneous injections of NT69L (1.0mg/kg). On days 1 and 21 the NT69L injection was followed 30 min later by treatment with either saline; the dopamine agonist, d-amphetamine (5.0mg/kg); or the serotonin 5-HT(2A) psychotomimetic receptor agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] DOI (0.5mg/kg). Experiments were repeated with either haloperidol (1mg/kg) or clozapine (20mg/kg) in place of NT69L. Acute injection of NT69L significantly blocked d-amphetamine and DOI disruption of PPI. As with the acute injection, 21 daily administrations of NT69L also blocked d-amphetamine- and DOI-induced disruption of PPI. The data show that animals do not develop tolerance to the antipsychotic-like effects of NT69L when tested in the PPI of the startle response. The persistent efficacy of NT69L with chronic treatment provides further support for the therapeutic use of neurotensin (NT) agonists to treat schizophrenia and possibly other disorders that are characterized by PPI deficits. The modulatory role of NT69L on the dopaminergic and serotonergic neurotransmission systems both of which are implicated in the pathophysiology of schizophrenia is discussed.
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PMID:Chronic NT69L potently prevents drug-induced disruption of prepulse inhibition without causing tolerance. 1980 Sep 22

Neurotensin (NT) is a 13 amino acid neurohormone and/or neuromodulator, located in the synaptic vesicles and released from the neuronal terminals in a calcium-dependent manner. This peptide is present among mammalian and nonmammalian species, mainly in the central nervous system and the gastrointestinal tract. Due to its neuroendocrine activity, NT has been related to the pathophysiology of a series of disorders, such as schizophrenia, drug-abuse, Parkinson's disease, cancer, stroke, eating disorders and other neurodegenerative conditions. Moreover, NT participates in the physiology of pain-induction, central blood pressure control and inflammation. NT also plays an important interactive role in all components of the hypothalamic-anterior pituitary circuit, which is mediated by an endocrine, paracrine or/and autocrine manner, towards most of the anatomical regions that define this circuit. A considerable amount of data implicates NT in thyroid-related regulation through this circuit, the exact mechanisms of which should be further investigated for the potential development of more targeted approaches towards the treatment of thyroid-related endocrine diseases. The aim of this study was to provide an up-to-date review of the literature concerning the regulatory role of NT on the hypothalamic-anterior pituitary axons, with an emphasis on the control of thyroid-related functions.
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PMID:The regulatory role of neurotensin on the hypothalamic-anterior pituitary axons: emphasis on the control of thyroid-related functions. 1987 95

An increasing number of putative therapeutic targets have been identified in recent years for the treatment of neuronal pathophysiologies including pain, epilepsy, stroke and schizophrenia. Many of these targets signal through calcium (Ca(2+)), either by directly facilitating Ca(2+) influx through an ion channel, or through activation of G proteins that couple to intracellular Ca(2+) stores or voltage-gated Ca(2+) channels. Immortalized neuronal cell lines are widely used models to study neuropharmacology. However, systematic pharmacological characterization of the receptors and ion channels expressed in these cell lines is lacking. In this study, we systematically assessed endogenous Ca(2+) signaling in response to addition of agonists at potential therapeutic targets in a range of cell lines of neuronal origin (ND7/23, SH-SY5Y, 50B11, F11 and Neuro2A cells) as well as HEK293 cells, a cell line commonly used for over-expression of receptors and ion channels. This study revealed a remarkable diversity of endogenous Ca(2+) responses in these cell lines, with one or more cell lines responding to addition of trypsin, bradykinin, ATP, nicotine, acetylcholine, histamine and neurotensin. Subtype specificity of these responses was inferred from agonist potency and the effect of receptor subtype specific antagonist. Surprisingly, HEK293 and SH-SY5Y cells responded to the largest number of agonists with potential roles in neuronal signaling. These findings have implications for the heterologous expression of neuronal receptors and ion channels in these cell lines, and highlight the potential of neuron-derived cell lines for the study of a range of endogenously expressed receptors and ion channels that signal through Ca(2+).
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PMID:Characterization of endogenous calcium responses in neuronal cell lines. 1988 31

Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy. Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia. Another current animal model utilizes non-competitive antagonists of the NMDA/glutamate receptor, such as the psychotomimetic phencyclidine (PCP). In the present study, we investigated the effects of NT69L on PCP-induced behavioral and biochemical changes in the rat. The top of an activity chamber was modified to allow us to perform microdialysis in rat brain, while simultaneously recording the locomotor activity of a rat. PCP injection significantly increased activity as well as the extracellular concentration of norepinephrine (NE), 5-HT, dopamine (DA), and glutamate in the medial prefrontal cortex (mPFC). Pretreating with NT69L blocked the PCP-induced hyperactivity as well as the increase of DA, 5-HT, NE, and glutamate in mPFC. Interestingly and unexpectedly, NT69L markedly increased glycine levels, while PCP was without effect on glycine levels. Thus, NT69L showed antipsychotic-like effects in this glutamate-based animal model for studying schizophrenia. Previous work from our group suggests that NT69L also has antipsychotic-like effects in dopaminergic and serotonergic rodent models. Taken together, these data suggest that NT69L in particular and NT receptor agonists in general, will be useful as broad-spectrum antipsychotic drugs.
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PMID:The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex. 1994 49

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.
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PMID: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. 2019 96

Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors, NTS1 and NTS2. The functional-anatomical interactions between NT, the mesotelencephalic dopamine system, and structures targeted by dopaminergic projections have been studied. The present study was conducted to determine the effects of NT receptor subtypes on dopaminergic function with the use of mice lacking either NTS1 (NTS1(-/-)) or NTS2 (NTS2(-/-)). Basal and amphetamine-stimulated locomotor activity was determined. In vivo microdialysis in freely moving mice, coupled with HPLC-ECD, was used to detect basal and d-amphetamine-stimulated striatal extracellular dopamine levels. In vitro radioligand binding and synaptosomal uptake assays for the dopamine transporters were conducted to test for the expression and function of the striatal pre-synaptic dopamine transporter. NTS1(-/-) and NTS2(-/-) mice had higher baseline locomotor activity and higher basal extracellular dopamine levels in striatum. NTS1(-/-) mice showed higher locomotor activity and exaggerated dopamine release in response to d-amphetamine. Both NTS1(-/-) and NTS2(-/-) mice exhibited lower dopamine D(1) receptor mRNA expression in the striatum relative to wild type mice. Dopamine transporter binding and dopamine reuptake in striatum were not altered. Therefore, lack of either NTS1 or NTS2 alters the dopaminergic system. The possibility that the dysregulation of dopamine transmission might stem from a deficiency in glutamate neurotransmission is discussed. The data strengthen the hypothesis that NT receptors are involved in the pathogenesis of schizophrenia and provide a potential model for the biochemical changes of the disease.
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PMID:Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice. 2021 Nov 91

Endogenous neurotensin (NT) has been implicated in brain processes relevant to schizophrenia as well as the therapeutic effects of antipsychotic drugs (APDs) used to treat this disorder. Converging evidence suggests that NT1 receptors mediate the antipsychotic-like effects of NT, such as prepulse inhibition (PPI) elevation. However, the role of NT2 receptors in these effects is not known. To investigate the contribution of NT2 receptors to the regulation of PPI, we measured baseline PPI and acoustic startle response (ASR), in male and female wild type (WT) and NT2 knockout (KO) mice. For comparison, we also measured locomotor activity. Baseline PPI was significantly elevated in both male (P<0.01) and female (P<0.01) NT2 KO compared to WT mice, while ASR was significantly decreased in KO mice of both genders (P<0.01). In contrast, female but not male KO mice exhibited significantly less baseline ambulations (P<0.05). These data support the regulation of baseline PPI, ASR and locomotor activity by endogenous NT acting at the NT2 receptor. Further studies investigating the role of NT2 receptors in the modulation of APD-like effects are warranted.
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PMID:Effects of neurotensin-2 receptor deletion on sensorimotor gating and locomotor activity. 2039 36

Neurotensin is a tridecapeptide that was isolated 15 years ago from bovine hypothalamus and, since then, has been shown to fulfill the major criteria that define a neurotransmitter/neuromodulator. There is considerable evidence that neurotensin interacts with mesencephalic dopamine systems. Anatomical and functional data indicate that neurotensin modulates dopamine neurotransmission at all levels along nigrostriatal and mesolimbic dopamine pathways. The peptide appears to functionally antagonize the effects that the amine exerts via both presynaptic (auto) and postsynaptic dopamine receptors. This confers a neuroleptic-like pharmacological profile to neurotensin. In addition, extensive neurotensin/dopamine colocalization occurs in a subpopulation of mesencephalic dopamine neurons that project to the prefrontal cortex. Recently, the neurotensin precursor has been shown to contain another neurotensin-like peptide, neuromedin N, that binds with high affinity to brain neurotensin receptors and displays some neuroleptic-like effects. Therefore, neuromedin N may be considered as a potential comodulator (with neurotensin) of dopamine functions. Given the implications of dopamine systems in certain neuropathological and psychotic disorders such as Parkinson's disease and schizophrenia it is likely, as already suggested by some experimental evidence, that neurotensin plays an important role in the etiology and pathogenesis of these diseases.
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PMID:Neurotensin modulates dopamine neurotransmission at several levels along brain dopaminergic pathways. 2050 6

Much evidence suggests that targeting the neurotensin (NT) system may provide a novel and promising treatment for schizophrenia. Our recent work shows that: NTS1 knockout (NTS1(-/-)) mice may provide a potential animal model for studying schizophrenia by investigating the effect of deletion NTS1 receptor on amphetamine-induced hyperactivity and neurochemical changes. The data indicate a hyper-dopaminergic state similar to the excessive striatal DA activity reported in schizophrenia. The present study was done to determine if NTS1(-/-) mice also have similar changes in behavior, in prefrontal neurotransmitters, and in protein expression, as observed in wild type (WT) mice treated with the psychotomimetic phencylclidine (PCP), an animal model for schizophrenia. Our results showed many similarities between untreated NTS1(-/-) mice and WT mice chronically treated with PCP (as compared with untreated WT mice): 1) lower PCP-induced locomotor activity; 2) similar avolition-like behavior in forced-swim test and tail suspension test; 3) lower prefrontal glutamate levels; 4) less PCP-induced dopamine release in medial prefrontal cortex (mPFC); and 5) down-regulation of mRNA and protein for DA D(1), DA D(2), and NMDAR2A in mPFC. Therefore, these data strengthen the hypothesis that the NTS1(-/-) mouse is an animal model of schizophrenia, particularly for the dysfunction of the prefrontal cortex. In addition, after chronic PCP administration, the DA D(1) receptor was up-regulated in NTS1(-/-) mice, results which suggest a possible interaction of NTS1/DA D(1) in mPFC contributing to chronic PCP-induced schizophrenia-like signs.
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PMID:Similarities in the behavior and molecular deficits in the frontal cortex between the neurotensin receptor subtype 1 knockout mice and chronic phencyclidine-treated mice: relevance to schizophrenia. 2065 57

Pre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) receptors. We hypothesized that the NT receptor agonist (NT69L) would prevent PPI disruption in mice challenged with d-amphetamine (10 mg kg(-1)) and dizocilpine (1 mg kg(-1)). We investigated the role of NTS1 and NTS2 in PPI using wild-type (WT), NTS1 (NTS1(-/-)) and NTS2 (NTS2(-/-)) knockout mice, via its disruption by psychotomimetic drugs, as well as the ability of clozapine and NT69L to block these PPI disruptions. There were no differences in baseline PPI across the three genotypes. d-Amphetamine and dizocilpine disrupted PPI in WT and NTS2(-/-) mice but not in NTS1(-/-) mice. In WT mice, clozapine (1 mg kg(-1)) and NT69L (1 mg kg(-1)) significantly blocked d-amphetamine-induced disruption of PPI. Similarly, in WT mice, clozapine significantly blocked dizocilpine-induced PPI disruption, but NT69L did not. In NTS2(-/-) mice clozapine blocked d-amphetamine-but not dizocilpine-induced PPI disruption, while NT69L blocked both d-amphetamine- and dizocilpine-induced PPI disruption. Our results indicate that NTS1 seems essential for d-amphetamine and dizocilpine disruption of PPI. Additionally, this report provides support to the hypothesis that NT analogs could be used as novel antipsychotic drugs.
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PMID:Sensorimotor gating in NTS1 and NTS2 null mice: effects of d-amphetamine, dizocilpine, clozapine and NT69L. 2111 4


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