| 1 | Mol. Psychiatry 2000 Mar 5: 208-12 |
|---|---|
| PMID | 10822351 |
| Title | Comparative sequencing of the proneurotensin gene and association studies in schizophrenia. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 2 | Mol. Psychiatry 2000 Mar 5: 208-12 |
| PMID | 10822351 |
| Title | Comparative sequencing of the proneurotensin gene and association studies in schizophrenia. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 3 | Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004 May 286: R927-34 |
| PMID | 14715495 |
| Title | Secretin depolarizes nucleus tractus solitarius neurons through activation of a nonselective cationic conductance. |
| Abstract | The recent suggestion that secretin may be useful in treating autism and schizophrenia has begun to focus attention on the mechanisms underlying this gut-brain peptide's actions in the central nervous system (CNS). In vitro autoradiographic localization of (125)I-secretin binding sites in rat brain shows the highest binding density in the nucleus tractus solitarius (NTS). Recent evidence suggests that intravenous infusion of secretin causes fos activation in NTS, a relay station playing important roles in the central regulation of autonomic functions. In this study, whole cell patch-clamp recordings were obtained from 127 NTS neurons in rat medullary slices. The mean resting membrane potential of these neurons was -54.7 +/- 0.3 mV, the mean input resistance was 3.7 +/- 0.2 GOmega, and the action potential amplitude of these neurons was always >70 mV. Current-clamp studies showed that bath application of secretin depolarized the majority (80.8%; 42/52) of NTS neurons tested, whereas the remaining cells were either unaffected (17.3%; 9/52) or hyperpolarized (1.9%; 1/52). These depolarizing effects were maintained in the presence of 5 microM TTX and found to be concentration dependent from 10(-12) to 10(-7) M. Using voltage-clamp techniques, we also identified modulatory actions of secretin on specific ion channels. Our results demonstrate that while secretin is without effect on net whole cell potassium curreNTS, it activates a nonselective cationic conductance (NSCC). These results show that NTS neurons are activated by secretin as a consequence of activation of a NSCC and support the emerging view that secretin can act as a neuropeptide within the CNS. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 4 | Am J Psychiatry 2004 Jun 161: 975-84 |
| PMID | 15169685 |
| Title | Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. |
| Abstract | Four studies using identical protocols evaluated the safety and efficacy of four novel, evidence-based targets for antipsychotic ageNTS: a neurokinin (NK(3)) antagonist (SR142801), a serotonin 2A/2C (5-HT(2A/2C)) antagonist (SR46349B), a central cannabinoid (CB(1)) antagonist (SR141716), and a neurotensin (NTS(1)) antagonist (SR48692). Adults with schizophrenia or schizoaffective disorder (N=481) were randomly assigned in a 3:1:1 ratio to receive fixed doses of investigational drug, placebo, or haloperidol for 6 weeks. Primary efficacy variables included changes from baseline in total score on the Positive and Negative Syndrome Scale, severity of illness score on the Clinical Global Impression (CGI), and total score and psychosis cluster score on the Brief Psychiatric Rating Scale (BPRS). Significantly greater improvement in all primary efficacy variables was seen in the group receiving haloperidol than in the group receiving placebo at 6 weeks (endpoint analyses), indicating the validity of the study. The group receiving the NK(3) antagonist showed significantly greater improvement over baseline than the group receiving placebo as measured by Positive and Negative Syndrome Scale total score, CGI severity of illness score, and BPRS psychosis cluster score. Reductions in the Positive and Negative Syndrome Scale total and negative scores in the group receiving the 5-HT(2A/2C) antagonist were significantly larger than those in the group receiving placebo. The improvemeNTS in psychopathology produced by the NK(3) and 5-HT(2A/2C) antagonists were smaller than those produced by haloperidol, although the response to the NK(3) antagonist was positively correlated with plasma levels. The groups receiving the CB(1) and NTS(1) antagonists did not differ from the group receiving placebo on any outcome measure. All investigational drugs were well tolerated. The novel design used in this study permitted the use of a smaller number of patieNTS receiving placebo to test the efficacy of the four novel compounds. The NK(3) and 5-HT(2A/2C) antagonists showed evidence of efficacy in the treatment of schizophrenia and schizoaffective disorder. Study limitations preclude a definitive conclusion on the efficacy of CB(1) and NTS(1) antagonists in the treatment of schizophrenia. Further study of these two promising nondopaminergic mechanisms to treat schizophrenia and schizoaffective disorder appears indicated. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 5 | J Neural Transm (Vienna) 2009 Aug 116: 923-39 |
| PMID | 19156349 |
| Title | Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of the forebrain: relevance for schizophrenia. |
| Abstract | Receptor-receptor interactions within receptor heterodimers and receptor mosaics formed by different types of GPCRs represent an important integrative mechanism for signaling in brain networks at the level of the plasma membrane. The malfunction of special heterodimers and receptor mosaics in the ventral striatum containing D(2) receptors and 5-HT(2A) receptors in cortical networks may contribute to disturbances of key pathways involving ventral striato-pallidal GABA neurons and mediodorsal thalamic prefrontal glutamate neurons that may lead to the development of schizophrenia. The ventral striatum transmits emotional information to the cerebral cortex through a D(2) regulated accumbal-ventral pallidal-mediodorsal-prefrontal circuit which is of special interest to schizophrenia in view of the reduced number of glutamate mediodorsal-prefrontal projections associated with this disease. This circuit is especially vulnerable to D(2) receptor activity in the nucleus accumbens, since it produces a reduction in the prefrontal glutamate drive from the mediodorsal nucleus. The following D(2) receptor containing heterodimers/receptor mosaics are of special interest to schizophrenia: A(2A)-D(2), mGluR5-D(2), CB(1)-D(2), NTS(1)-D(2) and D(2)-D(3) and are discussed in this review. They may have a differential distribution pattern in the local circuits of the ventral striato-pallidal GABA pathway, predominantly located extrasynaptically. Specifically, trimeric receptor mosaics consisting of A(2A)-D(2)-mGluR5 and CB(1)-D(2)-A(2A) may also exist in these local circuits and are discussed. The integration of receptor signaling within assembled heterodimers/receptor mosaics is brought about by agonists and allosteric modulators. These cause the intramembrane receptor-receptor interactions, via allosteric mechanisms, to produce conformational changes that pass over the receptor interfaces. Exogenous and endogenous cooperativity is discussed as well as the role of the cortical mGluR2-5-HT(2A) heterodimer/receptor mosaic in schizophrenia (Gonzalez-Maeso et al. 2008). Receptor-receptor interactions within receptor heterodimer/receptor mosaics of different receptors in the ventral striatum and cerebral cortex give novel strategies for treatment of schizophrenia involving, e.g., monotherapy with either A(2A), mGluR5, CB(1) or NTS(1) agonists or combined therapies with some of these agonists combined with D(2)-like antagonists that specifically target the ventral striatum. In addition, a combined targeting of receptor mosaics in the ventral striatum and in the cerebral cortex should also be considered. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 6 | CNS Neurosci Ther 2011 Oct 17: 333-44 |
| PMID | 21951367 |
| Title | Possible role of glia in cognitive impairment in schizophrenia. |
| Abstract | Cognitive impairment is a core disorder of the schizophrenia syndrome. Based on glial-neuronal interactions, a pathophysiological model is proposed that could be explanatory for cognitive impairment in schizophrenia. The model consists of three main hypotheses concerning the pathophysiology in tripartite synapses, oligodendrocyte-axonic interactions, and in the glial networks (astrocytic syncytium). In tripartite synapses nonfunctional astrocytic receptors may cause an unconstrained synaptic information flux, since they cannot be occupied by neurotransmitters (NTS). Therefore, a generalization of information processing may occur in the brain causing hallucinations, delusions, and thought disorder. If the oligodendrocyte-axonic system decomposes, the brain is unable to process information in qualitative domains or categories. This may lead to severe incoherence phenomena such as thought disorder. Supposing that in the astrocytic syncytium gap junctions (g.js) normally form plaques functioning as memory devices, loss of function of g.j. may also cause cognitive impairment, since the syncytium decomposes and g.j. plaques cannot be generated. These hypotheses are experimentally testable. Finally, the problem of treatment of patieNTS with schizophrenia is discussed, in case the presented model of schizophrenia might be verified. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 7 | Curr. Med. Chem. 2012 -1 19: 304-16 |
| PMID | 22335510 |
| Title | Relevance of dopamine D(2)/neurotensin NTS1 and NMDA/neurotensin NTS1 receptor interaction in psychiatric and neurodegenerative disorders. |
| Abstract | The existence of functional NT/dopamine interactions in the central nervous system has been extensively documented. Among others, a possible molecular mechanism underlying the NT-induced modulation of dopamine release is a direct antagonistic NTS(1)/D(2) receptor interaction. More recently, neurochemical experimeNTS also supported the existence of a possible interaction between NT and N-methyl-d-aspartate (NMDA) receptors. In particular, it has been suggested that NT, by amplifying NMDA receptor signaling, could be involved in neurodegeneration. The present article attempts to provide a summary of current knowledge, mainly emerging from our studies, on the existence of receptor-receptor interactions between NT receptor subtype 1 (NTS1) and dopamine D(2) or NMDA receptors in the brain. Special emphasis is placed on the pre and post-synaptic neurochemical mechanisms possibly underlying the involvement of these interactions in the physiopathology of schizophrenia and acute neurodegenerative disorders. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 8 | J. Proteome Res. 2012 Aug 11: 4338-50 |
| PMID | 22800120 |
| Title | Metabolomic analysis of biochemical changes in the plasma and urine of first-episode neuroleptic-naïve schizophrenia patients after treatment with risperidone. |
| Abstract | Early findings propose that impaired neurotransmission in the brain plays a key role in the pathophysiology of schizophrenia. Recent advances in understanding its multiple etiologies and pathogenetic mechanisms provide more speculative hypotheses focused on even broader somatic systems. Using a targeted tandem mass spectrometry (MS/MS)-based metabolomic platform, we compared metabolic signatures consisting of monoamine and amino acid neurotransmitter (NT) metabolites in plasma/urine simultaneously between first-episode neuroleptic-naïve schizophrenia patieNTS (FENNS) and healthy controls before and after a 6-week risperidone monotherapy, which suggest that the patient NT profiles are restoring during treatment. To detect and identify potential biomarkers associated with schizophrenia and risperidone treatment, we also performed a combined ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) and 1H nuclear magnetic resonance (NMR)-based metabolomic profiling of the same samples, indicating a further deviation of the patieNTS' global metabolic profile from that of controls. The NTS and their metabolites together with the 32 identified biomarkers underpin that metabolic pathways including NT metabolism, amino acid metabolism, glucose metabolism, lipid metabolism, energy metabolism, antioxidant defense system, bowel microflora and endocrine system are disturbed in FENNS. Among them, pregnanediol, citrate and ?-ketoglutarate (?-KG) were significantly associated with symptomatology of schizophrenia after Bonferroni correction and may be useful biomarkers for monitoring therapeutic efficacy. These findings promise to yield valuable insights into the pathophysiology of schizophrenia and may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 9 | Eur. J. Pharmacol. 2013 Dec 721: 201-7 |
| PMID | 24076181 |
| Title | Effects of the neurotensin NTS? receptor agonist PD149163 on visual signal detection in rats. |
| Abstract | Antipsychotic drugs provide limited efficacy for cognitive impairment in schizophrenia. Recent studies have found that the neurotensin NTS1 receptor agonist and putative atypical antipsychotic drug PD149163 reverses deficits in sensory-gating and novel object recognition, suggesting that this compound may have the potential to improve cognitive functioning in schizophrenia. The present study sought to extend these investigations by evaluating the effects of PD149163 on sustained attention using a visual signal detection operant task in rats. PD149163, the atypical antipsychotic drug clozapine, and the dopamine D2/3 receptor antagonist raclopride all significantly decreased percent "hit" accuracy, while none of these compounds altered "correct rejections" (compared to vehicle control). Clozapine and raclopride significantly increased response latency, while high doses of PD149163 and raclopride significantly increased trial omissions. Nicotine, which was tested as a positive control, significantly improved overall performance in this task and did not affect response latency or trial omissions. The present findings suggest that neurotensin NTS1 receptor agonists, like antipsychotic drugs, may inhibit sustained attention in this task despite having different pharmacological mechanisms of action. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 10 | Curr. Med. Chem. 2013 -1 20: 4217-40 |
| PMID | 23992313 |
| Title | 5'-nucleotidases, nucleosides and their distribution in the brain: pathological and therapeutic implications. |
| Abstract | ElemeNTS of the nucleoside system (nucleoside levels, 5'-nucleotidases (5'NTS) and other nucleoside metabolic enzymes, nucleoside transporters and nucleoside receptors) are unevenly distributed in the brain, suggesting that nucleosides have region-specific functions in the human brain. Indeed, adenosine (Ado) and non-Ado nucleosides, such as guanosine (Guo), inosine (Ino) and uridine (Urd), modulate both physiological and pathophysiological processes in the brain, such as sleep, pain, memory, depression, schizophrenia, epilepsy, Huntington's disease, Alzheimer's disease and Parkinson's disease. Interactions have been demonstrated in the nucleoside system between nucleoside levels and the activities of nucleoside metabolic enzymes, nucleoside transporters and Ado receptors in the human brain. Alterations in the nucleoside system may induce pathological changes, resulting in central nervous system (CNS) diseases. Moreover, several CNS diseases such as epilepsy may be treated by modulation of the nucleoside system, which is best achieved by modulating 5'NTS, as 'NTS exhibit numerous functions in the CNS, including intracellular and extracellular formation of nucleosides, termination of nucleoside triphosphate signaling, cell adhesion, synaptogenesis and cell proliferation. Thus, modulation of 5'NT activity may be a promising new therapeutic tool for treating several CNS diseases. The present article describes the regionally different activities of the nucleoside system, demonstrates the associations between these activities and 5'NT activity and discusses the therapeutic implications of these associations. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 11 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 287-94 |
| PMID | 23085507 |
| Title | Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. |
| Abstract | Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patieNTS with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangemeNTS. In addition, numerous previous studies have highlighted alterations in the immune system of patieNTS with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-?) appear to be state markers, whereas IL-12, interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patieNTS with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 12 | Neuroimage Clin 2014 -1 6: 463-74 |
| PMID | 25389520 |
| Title | Altered functional connectivity links in neuroleptic-naïve and neuroleptic-treated patients with schizophrenia, and their relation to symptoms including volition. |
| Abstract | In order to analyze functional connectivity in untreated and treated patieNTS with schizophrenia, resting-state fMRI data were obtained for whole-brain functional connectivity analysis from 22 first-episode neuroleptic-naïve schizophrenia (NNS), 61 first-episode neuroleptic-treated schizophrenia (NTS) patieNTS, and 60 healthy controls (HC). Reductions were found in untreated and treated patieNTS in the functional connectivity between the posterior cingulate gyrus and precuneus, and this was correlated with the reduction in volition from the Positive and Negative Symptoms Scale (PANSS), that is in the willful initiation, sustenance, and control of thoughts, behavior, movemeNTS, and speech, and with the general and negative symptoms. In addition in both patient groups interhemispheric functional connectivity was weaker between the orbitofrontal cortex, amygdala and temporal pole. These functional connectivity changes and the related symptoms were not treated by the neuroleptics. Differences between the patient groups were that there were more strong functional connectivity links in the NNS patieNTS (including in hippocampal, frontal, and striatal circuits) than in the NTS patieNTS. These findings with a whole brain analysis in untreated and treated patieNTS with schizophrenia provide evidence on some of the brain regions implicated in the volitional, other general, and negative symptoms, of schizophrenia that are not treated by neuroleptics so have implications for the development of other treatmeNTS; and provide evidence on some brain systems in which neuroleptics do alter the functional connectivity. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 13 | Exp Clin Psychopharmacol 2014 Dec 22: 541-7 |
| PMID | 25222546 |
| Title | Systemic administration of the neurotensin NTS?-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats. |
| Abstract | Agonists for the neurotensin NTS? receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS?-receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS? agonists have reported improvemeNTS in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, which suggest an ability of NTS?-receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS?-receptor activation on learning and memory consolidation in male Long-Evans and Brown Norway rats using a delayed nonmatch-to-position task radial arm-maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following 3-, 7-, and 24-hr delay, whereas Long-Evans rats exhibited an increase in spatial memory errors following only a 7-, and 24-hr delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hr delay. Administration of the NTS(1/2)-receptor antagonist SR142948 prior to the information trial did not affect retention-trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, the results of this study support previous findings suggesting that NTS?-receptor agonists may improve some aspects of cognitive functioning. |
| SCZ Keywords | schizophrenia, schizophrenics |