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)

The possibility that the neuropeptide neurotensin (NT) may function as an endogenous antipsychotic compound was first hypothesized almost two decades ago. Since that time, considerable effort has been directed towards determining whether NT neurons mediate the effects of antipsychotic drugs (APDs). The anatomic, biochemical, behavioral, and clinical relevance of this hypothesis is reviewed. Although the majority of the available evidence is indirect, the availability of several NT receptor (NTR) antagonists have now made possible the direct examination of the involvement of the NT system in the mechanism of action of APDs. Preliminary studies in our laboratory demonstrate the ability of a selective NTR antagonist to block the effects of APDs in two models of sensory motor gating deficits characteristic of schizophrenia. These data, taken together with a compelling series of studies demonstrating that increases of NT/neuromedin N mRNA expression and NT content in the nucleus accumbens and striatum after chronic administration of APDs are predictive of clinical efficacy and extrapyramidal side effects, respectively, provide direct preclinical evidence for a role of the NT system in the clinical efficacy of APDs. Although effects of selective NTR antagonists in normal volunteers or schizophrenic patients have not been studied, and nonpeptidergic NTR agonists have not yet been identified, these cumulative results provide the groundwork for the use of NT-ergic compounds in the treatment of schizophrenia.
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PMID:Does neurotensin mediate the effects of antipsychotic drugs? 1043 99

The neurotensin receptor 1 (NTR1) subtype belongs to the family of G protein-coupled receptors and mediates most of the known effects of the neuropeptide including modulation of central dopaminergic transmission. This suggested that nonpeptide agonist mimetics acting at the NTR1 might be helpful in the treatment of Parkinson's disease and schizophrenia. Here, we attempted to define the molecular interactions between neurotensin-(8-13), the pharmacophore of neurotensin, and the rat NTR1. Mutagenesis of the NTR1 identified residues that interact with neurotensin. Structure-activity studies with neurotensin-(8-13) analogs identified the peptide residues that interact with the mutated amino acids in the receptor. By taking these data into account, computer-assisted modeling techniques were used to build a tridimensional model of the neurotensin-(8-13)-binding site in which the N-terminal tetrapeptide of neurotensin-(8-13) fits in the third extracellular loop and the C-terminal dipeptide binds to residues at the junction between the extracellular and transmembrane domains of the receptor. Interestingly, the agonist binding site lies on top of the previously described NTR1-binding site for the nonpeptide neurotensin antagonist SR 48692. Our data provide a basis for understanding at the molecular level the agonist and antagonist binding modes and may help design nonpeptide agonist mimetics of the NTR1.
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PMID:Identification of residues involved in neurotensin binding and modeling of the agonist binding site in neurotensin receptor 1. 1061 22

In the present study we describe the excitatory effects of the bioactive peptide neurotensin on the electrical activity of dopamine neurons (simultaneously recorded) in the substantia nigra pars compacta and the ventral tegmental area. The neurotensin fragment (8-13) induced comparable increases in firing rate of the substantia nigra and ventral tegmental area dopamine neurons (EC50 values 30 and 45 nM, respectively). The neurotensin receptor antagonist SR142948A antagonized the excitatory effects of neurotensin fragment (8-13) (pA2 values 8.4 and 8.2, respectively). Furthermore, it was found that a low concentration of neurotensin fragment (8-13) (1 nM) attenuated the inhibition of the firing rate by the selective dopamine D2 receptor agonist quinpirole in both neuron types (e.g., the effect of 0.01 microM quinpirole was reduced by approximately 60% in the presence of 1 nM neurotensin fragment [8-13]). Antagonism of this neurotensin fragment (8-13) effect by SR142948A confirms that neurotensin receptors can reduce the effect of dopamine D2 receptors at the single-cell level. These results are discussed in the light of possible roles for neurotensin in neurological disorders such as Parkinson's disease and schizophrenia.
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PMID:Neurotensin attenuates the quinpirole-induced inhibition of the firing rate of dopamine neurons in the rat substantia nigra pars compacta and the ventral tegmental area. 1065 21

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

This study was designed to investigate the possible involvement of members of the nuclear receptor family of transcription factors in the effects of antipsychotic drugs used in the treatment of schizophrenia. We have identified, using RT-PCR screening, an important modulation of nerve growth factor-inducible B (NGFI-B) mRNA levels by typical and atypical neuroleptics in the rat forebrain. NGFI-B, a member of the nuclear receptor family, can be observed in target structures of dopaminergic pathways. Using in situ hybridization, we also demonstrate that typical and atypical antipsychotics induced contrasting patterns of expression of NGFI-B after both acute and chronic administration. An acute treatment with clozapine or haloperidol induces high NGFI-B mRNA levels in the prefrontal and cingulate cortices and in the nucleus accumbens shell. However, haloperidol, but not clozapine, dramatically increases NGFI-B expression in the dorsolateral striatum. In contrast, chronic treatment with clozapine reduces NGFI-B expression below basal levels in the rat forebrain, whereas haloperidol still induces high NGFI-B mRNA levels in the dorsolateral striatum. Finally, using a double in situ hybridization technique, we show that acute administration of both neuroleptics increases NGFI-B expression in neurotensin-containing neurons in the nucleus accumbens shell, whereas the effects of haloperidol in the dorsolateral striatum are mainly observed in enkephalin-containing neurons. These results are the first demonstration that members of the nuclear receptor family of transcription factors could play an important role in the effects of antipsychotic drugs.
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PMID:Contrasting patterns and cellular specificity of transcriptional regulation of the nuclear receptor nerve growth factor-inducible B by haloperidol and clozapine in the rat forebrain. 1098 52

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

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.
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PMID:Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating. 1116 Apr 39

Interactions between the classical monoamine neurotransmitter dopamine (DA) and the peptide neurotransmitter neurotensin (NT) in the central nervous system (CNS) have now been investigated for over two decades. Interest in this topic has been sustained, primarily because of the potential clinical relevance of these interactions to schizophrenia and drug abuse. In the past five years, important new discoveries in the NT field have markedly expanded our previous database. Additional NT receptors have been cloned, and novel and refined techniques have contributed to a more detailed description of the anatomy of the CNS NT system. Additionally, lipophilic NT receptor antagonists, active in the CNS after peripheral administration, have rendered more facile the investigation of the physiologic importance of endogenous NT at electrophysiologic, neurochemical, and behavioral levels. In the present review, the discussion of NT/DA interactions will progress from a discussion of the anatomical interactions between these two systems, to electrophysiologic and neurochemical interactions, and finally to behavioral implications-always with focus toward the potential clinical relevance of the data. The discussion of interactions between NT and DA systems will be limited to those occurring within the CNS. Moreover, because the DA projections from the midbrain to the striatum account for the bulk of the DA innervation in the CNS, we will focus on NT/DA interactions within these brain regions. Last, because of the extensive literature on NT/DA interactions available in the rat, our discussion will be based primarily on studies using this species.
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PMID:Neurotensin and dopamine interactions. 1173 15

Unlike disorders of other fields of medicine (eg., diabetes, heart disease), schizophrenia has been only marginally impacted by the study of animal models. This gap reflects the incomplete understanding of the causes and mechanisms of schizophrenia and the resulting lack of defined targets for model development. However, prior attempts at modeling in animals the complex symptoms of schizophrenia have given way to more promising component models. This review will address the evolving field of animal models of schizophrenia with a focus on models of errors in neurotransmission, and of psychophysiological deficits, with a concluding discussion of the present and future promise of genetic-based models. Evolving models based on the long-held conceptualization of schizophrenia as being based on errors in neurotransmission are discussed as regards the integration of newer findings implicating alterations in dopamine, glutamate and neurotensin function in the pathophysiology and pharmacotherapy of schizophrenia. The case for the more recent conceptualization of schizophrenia as a core deficit in information processing and stimulus filtering is discussed. Animal behavioral paradigms that model psychophysiologic constructs of stimulus processing deficits related to schizophrenia include prepulse inhibition (PPI), a model of sensorimotor gating, or latent inhibition (LI), a model of salience learning. These models represent both better supported associations with schizophrenia and more productive targets and are providing important new information regarding the psychopharmacology of schizophrenia. Genetic models of schizophrenia are based on the demonstrated heritability of the disorder and more recent pharmacogenetic findings for antipsychotic medications. Genetic-based animal models use behavioral or molecular genetic techniques to manipulate behaviors related to schizophrenia by altering the frequencies of related genes. The future development of increasingly informative animal models of schizophrenia will be dependent on a more complete understanding of schizophrenia, an integration of findings across animal models and refinements in the criteria used to assess model "validity" that better reflect the changing nature and roles of animal models of schizophrenia.
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PMID:The changing roles and targets for animal models of schizophrenia. 1174 40

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


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