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, an endogenous peptide and putative neurotransmitter, exhibits a wide range of interactions with dopaminergic neurons and displays some actions akin to neuroleptics. Moreover, neurotensin receptors are abundant in specific layers of the entorhinal cortex where cytoarchitectural abnormalities have been reported in schizophrenia. We therefore examined the entorhinal cortex from postmortem specimens of five control patients and six schizophrenic patients for alterations in neurotensin receptor quantitation and distribution using receptor autoradiography. Specific 125I- neurotensin binding was concentrated in layer II cell clusters, with a 40% reduction in binding in the schizophrenic group (p < 0.05). Moderate binding was observed in both cohorts in deep layers V/VI, with negligible binding in the hippocampus. There was no statistical difference in quantitative neurotensin binding in other lamina of the entorhinal cortex of schizophrenics compared with controls. The characteristic laminar pattern of binding did not differ between cohorts. The reduction in neurotensin binding in schizophrenics is consistent with an increasing number of reports of structural abnormalities in the medial temporal lobe of schizophrenics in general and the entorhinal cortex in particular. Further studies are required to examine the evidence for neuroanatomic and neurochemical pathology in the entorhinal cortex.
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PMID:Autoradiographic characterization of neurotensin receptors in the entorhinal cortex of schizophrenic patients and control subjects. 878 24

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 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

Despite evidence from a variety of experimental approaches implicating the neuropeptide neurotensin in both the mechanism of action of antipsychotic drugs and the pathophysiology of schizophrenia, there has been some debate as to whether a peripherally administered neurotensin receptor agonist represents a sound strategy for the development of a novel class of antipsychotic drugs.
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PMID:Neurotensin: an endogenous antipsychotic? 1178 16

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

The dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) shell is implicated in schizophrenia and in psychostimulant-induced drug-seeking behavior, both of which are affected by activation of the functionally opposed high-affinity neurotensin receptor (NTS1). To determine the functionally relevant sites, we examined the dual electron microscopic immunocytochemical localization of D2R and NTS1 in the NAc shell of rat brain. Immunolabeling for each receptor was seen in association with cytoplasmic organelles, or more rarely, on the plasma membrane of both axonal and somatodendritic profiles. Some of the axonal and many of the dendritic processes colocalized the two receptors. The dually labeled axon terminals often formed symmetric synapses or appositional contacts with unlabeled dendritic profiles. The morphology of these terminals suggests that they contain either inhibitory amino acids or dopamine. Other axonal profiles expressing exclusively NTS1 or D2R were without synaptic specializations or formed asymmetric, excitatory-type synapses mainly on unlabeled dendritic spines. In addition, however, several D2R-immunoreactive terminals were observed presynaptic to dendrites containing NTS1. The somatodendritic profiles immunolabeled for NTS1 and/or D2R had morphological features typical of inhibitory spiny projection neurons in the NAc. These results suggest that activation of NTS1 and D2R can dually modulate transmitter release from the same or separate phenotypically distinct axon terminals in the NAc shell. These presynaptic receptors as well as the postsynaptic NTS1 distribution in neurons that also contain or receive input from terminals containing D2R may mediate the opposing actions of neurotensin and dopamine in the NAc.
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PMID:Electron microscopic dual labeling of high-affinity neurotensin and dopamine D2 receptors in the rat nucleus accumbens shell. 1506 18

Converging data suggest a dysfunction of prefrontal cortical GABAergic interneurons in schizophrenia. Morphological and physiological studies indicate that cortical GABA cells are modulated by a variety of afferents. The peptide transmitter neurotensin may be one such modulator of interneurons. In the rat prefrontal cortex (PFC), neurotensin is exclusively localized to dopamine axons and has been suggested to be decreased in schizophrenia. However, the effects of neurotensin on cortical interneurons are poorly understood. We used in vivo microdialysis in freely moving rats to assess whether neurotensin regulates PFC GABAergic interneurons. Intra-PFC administration of neurotensin concentration-dependently increased extracellular GABA levels; this effect was impulse dependent, being blocked by treatment with tetrodotoxin. The ability of neurotensin to increase GABA levels in the PFC was also blocked by pretreatment with 2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-yl)carbonylamino]tricyclo(3.3.1.1 [EC] .3.7)decan-2-carboxylic acid (SR48692), a high-affinity neurotensin receptor 1 (NTR1) antagonist. This finding is consistent with our observation that NTR1 was localized to GABAergic interneurons in the PFC, particularly parvalbumin-containing interneurons. Because neurotensin is exclusively localized to dopamine axons in the PFC, we also determined whether neurotensin plays a role in the ability of dopamine agonists to increase extracellular GABA levels. We found that D2 agonist-elicited increases in PFC GABA levels were blocked by pretreatment with SR48692, consistent with data indicating that D2 autoreceptor agonists increase neurotensin release from dopamine-neurotensin axons in the PFC. These findings suggest that neurotensin plays an important role in regulating prefrontal cortical interneurons and that it may be useful to consider neurotensin agonists as an adjunct in the treatment of schizophrenia.
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PMID:Neurotensin activates GABAergic interneurons in the prefrontal cortex. 1571 98

P75(NTR) is a common neurotrophin receptor which binds all neurotrophins with similar affinities and has been shown to be capable of mediating programmed cell death. In this study, we investigated effects of the antipsychotic drugs (APDs) haloperidol, clozapine, quetiapine, and risperidone on p75(NTR) mRNA levels in PC12 cells. Haloperidol is a prototype of typical APDs, and the other three drugs are atypical APDs, which are effective in reducing negative symptoms and cognitive deficits of schizophrenia, cause less side effects, and are more tolerable compared to haloperidol. PC12 cells were cultured with various concentrations of haloperidol, clozapine, quetiapine, or risperidone, in their media. After culture for 48h, the cell viabilities and p75(NTR) mRNA levels were measured. It was shown that both haloperidol and the atypical APDs used in this study deceased p75(NTR) mRNA levels in PC12 cells in a dose dependent manner, while not affecting cell viabilities. In further experiments, doses that produced significant/greatest effects were chosen and provided in the culture media for various periods. Decreases in p75(NTR) mRNA levels were observed in cultures treated for 12h with quetiapine, 24h with clozapine or risperidone, or for 48h with haloperidol. These results suggest that both haloperidol and atypical APDs have the same action of decreasing p75(NTR) mRNA levels in PC12 cells. Although the underlying molecular mechanism of this action remains to be elucidated, this finding is particularly relevant given the neurodevelopmental deficits associated with schizophrenia and important roles of p75(NTR) in mediating cell death.
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PMID:Haloperidol and atypical antipsychotics share a same action of decreasing P75(NTR) mRNA levels in PC12 cells. 1651 40


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