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)

Neurotensin is a neuropeptide which coexists with mesolimbic dopamine and has exhibited neuroleptic-like activity in the nucleus accumbens. This study examined the effects of neurotensin infused into the nucleus accumbens on prepulse inhibition (PPI) of the rat's acoustic startle reflex, a measure which is relevant to the sensorimotor gating deficits seen in schizophrenia. Neurotensin (5 micrograms) had no effect on the amplitude of the acoustic startle reflex nor on baseline PPI, but it potentiated the disruption of PPI produced by amphetamine and apomorphine. This is the first report of a pro-dopamine action for intra-accumbens neurotensin, and suggests that a complex behavioral pharmacology is associated with this neuropeptide.
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PMID:Pro-dopamine effects of neurotensin on sensorimotor gating deficits. 939 52

Neurotensin (NT) is an endogenous tridecapetide1 cleaved from a precursor proneurotensin/ proneuromedin protein. NT localises within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems1-3 and it is now clear that NT can selectively modulate dopaminergic neurotransmission.2-9 These anatomical and functional connections have led to the hypothesis that NT dysfunction might contribute to the pathogenesis of neuropsychiatric disorders in which disordered dopaminergic neurotransmission is suspected, particularly schizophrenia.3 The latter hypothesis has been supported circumstantially by the observation that central administration of NT produces effects similar to those produced by the peripheral administration of atypical antipsychotics,10,11 and more directly by studies showing levels of NT in cerebral spinal fluid (CSF) is lower in schizophrenics than in controls.12,13 To allow such hypotheses to be tested, we used denaturing high performance liquid chromatography (DHPLC)14 to identify three sequence variants in the neurotensin gene (NTS) that might alter NT structure or expression. However, using a case-control study design and a novel genotyping system based upon a primer extension protocol and HPLC detection,15 we found no evidence to support the hypothesis that variation in the proneurotensin gene contributes to susceptibility to schizophrenia.
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PMID:Comparative sequencing of the proneurotensin gene and association studies in schizophrenia. 1082 51

Neurotensin and its high affinity receptor (NTSR1) localise within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems and it is now clear that neurotensin can selectively modulate dopaminergic neurotransmission. This has led to the hypothesis that altered neurotensin function contributes to the pathogenesis of schizophrenia and other psychoses. This hypothesis has been supported circumstantially by a number of lines of evidence. (1) Central administration of neurotensin produces effects similar to those produced by the peripheral administration of atypical antipsychotics. (2) Observations of low levels of neurotensin in the CSF of schizophrenics. (3) Reduced numbers of neurotensin receptors in the brains of schizophrenics. Given the above link between neurotensin and dopamine, and the evidence implicating altered neurotensin function in psychosis, we have postulated that DNA sequence variation in neurotensin or its receptors might be associated with schizophrenia. In keeping with this hypothesis, an association has recently been reported between schizophrenia and the gene encoding the neurotensin high affinity receptor (NTSR1). However, caution is required because the associated marker, a tetranucleotide repeat, is located 3 kb away from the 3' end of the gene and there is no evidence that it is functional. Therefore, as a follow-up to our earlier work on neurotensin, we have now sought to test the hypothesis that DNA sequence variants that alter the structure or expression of the NTSR1 gene (VAPSEs) are associated with schizophrenia. However, while we found 14 novel sequence variants in 28 probands with psychosis, none resulted in an amino acid change, and neither direct nor indirect association studies suggested these are involved in susceptibility to schizophrenia.
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PMID:The high affinity neurotensin receptor gene (NTSR1): comparative sequencing and association studies in schizophrenia. 1103 91

It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather pathologic alterations of several interacting systems. Targeting of neuropeptide neuromodulator systems, capable of concomitantly regulating several transmitter systems, represents a promising approach for the development of increasingly effective and side effect-free antipsychotic drugs. Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be dysregulated in this disorder. Clinical studies in which cerebrospinal fluid (CSF) NT concentrations have been measured revealed a subset of schizophrenic patients with decreased CSF NT concentrations that are restored by effective antipsychotic drug treatment. Considerable evidence also exists concordant with the involvement of NT systems in the mechanism of action of antipsychotic drugs. The behavioral and biochemical effects of centrally administered NT remarkably resemble those of systemically administered antipsychotic drugs, and antipsychotic drugs increase NT neurotransmission. This concatenation of findings led to the hypothesis that NT functions as an endogenous antipsychotic. Moreover, typical and atypical antipsychotic drugs differentially alter NT neurotransmission in nigrostriatal and mesolimbic dopamine (DA) terminal regions, and these effects are predictive of side effect liability and efficacy, respectively. This review summarizes the evidence in support of a role for the NT system in both the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs.
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PMID:The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs. 1174 41

Neurotensin (NT) may play a role in the pathophysiology of schizophrenia and in the mechanism of action of antipsychotic drugs. Here we studied the effects of a 30-day regimen of haloperidol (1.15 mg/100 g food) and risperidone (1.15 and 2.3 mg/100 g food) on NT-like immunoreactivity (-LI) levels in brain tissue and NT-LI efflux in the ventral striatum (VSTR) of the rat. Haloperidol, but not risperidone, increased NT-LI levels in the striatum. In the occipital cortex, risperidone, but not haloperidol, decreased levels of NT-LI. In the hippocampus and the frontal cortex both haloperidol and risperidone (the higher dose) increased NT-LI levels. In the VSTR, haloperidol and risperidone (the higher dose) decreased NT-LI efflux and abolished the stimulatory effect of d-amphetamine (1.5 mg/kg, s.c.). Thus, changes in NT occur in response to antipsychotic drugs and psychostimulants that may be relevant for the pathophysiology and treatment of schizophrenia.
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PMID:Effects of haloperidol and risperidone on neurotensin levels in brain regions and neurotensin efflux in the ventral striatum of the rat. 1192 84

Neurotensin (NT) is a brain-gut tridecapeptide that fulfils a dual function, as a neurotransmitter/neuromodulator in the nervous system, and as a paracrine and circulating hormone in the periphery. Three NT receptors, NTS1, NTS2 and NTS3, have been cloned to date. NTS1 and NTS2 belong to the family of G protein-coupled receptors with seven transmembrane domains, whereas NTS3 is a single transmembrane domain protein that belongs to a recently identified family of sorting receptors. Most of the known peripheral and central effects of NT are mediated through NTS1. NTS2 might take part in the analgesic response elicited by central administration of NT; the biological roles of NTS3 are yet to be discovered. Most NT agonists and non-peptide antagonists developed to date have been studied for their NTS1-targeting abilities. Here, we will discuss the potential diagnostic and therapeutic uses of these compounds in cancer, schizophrenia, obesity and pain suppression.
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PMID:Targeting neurotensin receptors with agonists and antagonists for therapeutic purposes. 1263 Feb 97

Neurotensin has been implicated in the pathophysiology of schizophrenia. The neonatal amygdala lesion in rat has been proposed to be a neurodevelopmental model for some aspects of schizophrenia. [125I] Neurotensin binding was assessed in adult rats using in vitro autoradiography following a lesion of the basolateral amygdala at postnatal day 7 (Pd 7) or postnatal day 21 (Pd 21). The Pd 7 and Pd 21 lesions differentially affected neurotensin receptor densities in the hippocampal complex and (less pronounced) in the dopaminergic cell regions, implying a neurodevelopmental cause. These results may be of relevance for the involvement of neurotensin in the pathogenesis of schizophrenia.
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PMID:Effects of neonatal amygdala lesions on [125I] neurotensin binding in specific brain areas of adult rat. 1267 Mar 22

Neurotensin (NT) is a neuropeptide found in the central nervous system and gastrointestinal tract. It is closely associated with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT in various neuropsychiatric disorders. Because NT is readily degraded by peptidases, our group has developed various NT agonists that can be injected systemically, cross the blood brain barrier (BBB), yet retain the characteristics of native NT. The most widely studied and successful of these compounds, called NT69L, holds promise as a therapeutic agent for Parkinson's disease, schizophrenia, psychostimulant abuse and nicotine dependence, and serves as a tool to study the cellular and molecular effects of NT.
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PMID:Current topics: brain penetrating neurotensin analog. 1451 64

Neurotensin is a linear tridecapeptide that elicits a variety of physiological responses in the brain, including hypothermia and antinociception, and reduced levels have been linked to schizophrenia. Previously in our laboratory we developed a truncated neurotensin derivative, KK13. This hexapeptide exhibited key pharmacokinetic and behavioural characteristics of an antipsychotic and elicited central effects after oral administration. To examine the potential mechanism(s) of uptake, a radioactive analogue of KK13 (*KK13) was synthesized, characterized, and evaluated in the Caco-2 cell model of the human intestinal epithelium. Results suggested that uptake of *KK13 was a time-dependent passive process. A general linear trend in uptake was demonstrated over the concentration range (10 microM-1 m M) tested, and uptake was neither pH- nor sodium-dependent. Finally, after 60 min, intact *KK13 was identified associated with the cell components, providing further evidence for uptake and stability of the peptide.
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PMID:Cellular uptake of a radiolabelled analogue of neurotensin in the Caco-2 cell model. 1580 88

Neurotensin (NT) is a 13 amino acid neuropeptide that is found in the central nervous system and in the gastrointestinal tract. In brain, this peptide is prominently associated anatomically with dopaminergic, as well as other neurotransmitter systems. Based on animal studies, already decades old, researchers have hypothesised that NT receptor agonists will have antipsychotic properties in patients. However, to date no one has obtained a non-peptide NT receptor agonist. Therefore, there has been great interest in obtaining peptide analogues of NT, that, unlike NT resist degradation by peptidases and cross the blood-brain barrier, yet have the pharmacological characteristics of native NT, for therapeutic use in the treatment of schizophrenia, as well as other neuropsychiatric diseases such as Parkinson's disease and addiction to psychostimulants. In this review, we present the rationale for development of NT receptor agonists for treatment of certain central nervous system diseases, as well as a review of those peptide agonists that are in early stages of development.
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PMID:Neurotensin agonists as an alternative to antipsychotics. 1588 13


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