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 (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

Prepulse inhibition (PPI) of the acoustic startle reflex is a commonly used measure of preattentive sensorimotor gating. Disrupted PPI in rodents represents an animal model of the sensorimotor gating deficits characteristic of schizophrenia. The neurotensin (NT) system is implicated in the pathophysiology of schizophrenia, and NT has been hypothesized to act as an endogenous antipsychotic. In rats, NT receptor agonists restore PPI disrupted by dopamine receptor agonists and N-methyl-D-aspartate receptor antagonists, and pretreatment with an NT receptor antagonist blocks restoration of isolation rearing induced deficits in PPI by some antipsychotic drugs. The current studies further scrutinized the role of the NT system in the regulation of PPI and in antipsychotic drug-induced restoration of PPI using NT-null mutant mice (NT-/-). NT-/- mice exhibited significantly higher pulse alone startle amplitudes and disrupted PPI compared with NT+/+ mice. Haloperidol (0.1 mg/kg) and quetiapine (0.5 mg/kg) administered 30 min before PPI testing significantly increased PPI in NT+/+ mice but had no effect on PPI in NT-/- mice. In contrast, clozapine (1.0 mg/kg) significantly increased PPI in both NT-/- and NT+/+ mice, whereas olanzapine (0.5 mg/kg) had no effect on PPI in either NT-/- or NT+/+ mice. In a separate experiment, amphetamine (2.0 mg/kg i.p.) significantly disrupted PPI in NT+/+ mice but not NT-/- mice. These results provide evidence that the effects of antipsychotic drugs (APDs) may be differentially affected by the state of NT neurotransmission and, moreover, that APDs differ in their dependence on an intact NT system.
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PMID:Neurotensin-deficient mice have deficits in prepulse inhibition: restoration by clozapine but not haloperidol, olanzapine, or quetiapine. 1598 29

Midbrain dopaminergic (DA) neurones sustain important physiological functions such as control of motricity, signalling of the error in prediction of rewards and modulation of emotions and cognition. Moreover, their degeneration leads to Parkinson's disease and they may be dysfunctional in other pathological states, such as schizophrenia and drug abuse. A subset of DA neurones has been known for many years to contain releasable peptides such as neurotensin and cholecystokinin. However, recent experimental evidence indicates that the phenotype of DA neurones may be much more diverse, since it is suggested that, under certain conditions, they may also release glutamate, cannabinoids and even serotonin.
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PMID:Dopaminergic neurones: much more than dopamine? 1602 40

Addiction to psychostimulant drugs such as nicotine, amphetamine, and cocaine is a serious public health problem for which there is a paucity of accepted forms of pharmacotherapy. Nicotine dependence has become more frequently associated with psychiatric illness in recent decades, and patients who have schizophrenia are at highest risk and have the poorest prognosis for stopping their addiction. Possible mechanisms for this association include self-medication, with nicotine attenuating attentional deficits and negative symptoms. Neurotensin has been postulated to be an endogenous neuroleptic, and the performance of neurotensin analogues in animal models of addiction makes such compounds intriguing candidates for treatment of addiction in high-risk psychiatric populations.
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PMID:Neurobiologic basis of nicotine addiction and psychostimulant abuse: a role for neurotensin? 1612 77

Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role in motor and cognitive function. However, the impairment of emotional processes in neurologic and psychiatric pathologies involving the dopaminergic system (Parkinson disease, schizophrenia, autism, Attention Deficit Hyperactivity Disorder, Huntington disease, frontal lobe lesions), as well as the influence that administration of dopaminergic agonists/antagonists exert on the processing of emotion, suggest a role for DA in emotional processes. Moreover, emotional processes are dependent upon a variety of structures, the majority of which form part of the limbic system and are subject to DA innervation. In reviewing the literature, the amygdala emerges as a brain structure critical for emotional processing. It may also be implicated in deficits in emotional recognition found in two major disorders where DA's implication is clear: Parkinson disease and schizophrenia. In addition, the amygdala's response to emotional tasks is likely to be altered by the administration of both agonist and antagonist dopaminergic drugs. Experimental studies reinforce the idea of a dopaminergic contribution to emotional response, as suggested by biochemical, pharmacologic, and lesion experiments. Although the implication of the dopaminergic system in emotional processing appears to be clearly documented, the contribution of specific DA receptor subtypes, or of the DA cotransmitters cholecystokinin and neurotensin, or even glutamate, is, however, still unclear. Altogether, these observations suggest that DA has, undoubtedly, a direct and/or indirect role in the full emotional process.
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PMID:Dopaminergic contribution to the regulation of emotional perception. 1623 63

We have reported that acute d-amphetamine increases extracellular concentrations (efflux) of neurotensin-like immunoreactivity (NT-LI) and neuropeptide Y-LI (NPY-LI) in the ventral striatum (VSTR) of freely moving rats, effects that are abolished by chronic administration of haloperidol and risperidone admixed to food pellets. In this study we further investigated the d-amphetamine effects on NT-LI and NPY-LI efflux in VSTR and their content in selected brain regions. Rats received haloperidol, risperidone or vehicle for 30days and saline or d-amphetamine either on days 22-29 and/or day 30. Seven day d-amphetamine administration decreased basal NT-LI and NPY-LI efflux in vehicle-treated rats; pretreatment with haloperidol counteracted these effects, while pretreatment with risperidone had effect only on NT-LI. Acute d-amphetamine after the seven day d-amphetamine increased NT-LI only. Pretreatment with haloperidol or risperidone abolished the effects of acute d-amphetamine on NT-LI and NPY-LI. Acute and seven day d-amphetamine increased NT-LI and NPY-LI contents in striatum; seven day d-amphetamine also increased NT-LI in frontal and occipital cortex and both NT-LI and NPY-LI in hippocampus. Our results suggest that NT and NPY are involved in both the pathophysiology and the therapeutics of schizophrenia.
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PMID:Effects of acute and subchronic d-amphetamine on ventral striatal concentrations of neurotensin and neuropeptide Y in rats treated with antipsychotic drugs. 1652 2

Evidence implicating neural circuits that utilize the neuropeptide transmitter neurotensin (NT) in the pathophysiology of schizophrenia and in the mechanism of action of antipsychotic drugs has previously been reviewed. The majority of evidence, taken together, supports the development of NT receptor agonists as novel antipsychotic drugs. This review comprehensively describes the NT receptor subtypes, discusses the development of NT receptor agonists and the behavioral effects of currently available NT receptor agonists. The compilation of data suggests that NT receptor agonists may represent a novel class of antipsychotic drugs for the treatment of schizophrenia.
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PMID:Novel treatments of schizophrenia: targeting the neurotensin system. 1661 Oct 93

The peptide neurotensin has been studied for more than 30 years. Although it is widely distributed in the central and peripheral nervous systems, neurotensin has been more intensely studied with regard to its interactions with the central dopamine system. A number of claims have been made regarding its possible implication in many diseases of the central nervous system, including schizophrenia. In this review, we describe briefly the basic biology of this neuropeptide, and then we consider the strengths and the weaknesses of the data that suggest a role for neurotensin in schizophrenia, drug abuse, Parkinson's disease, pain, central control of blood pressure, eating disorders, cancer, neurodegenerative disorders and inflammation.
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PMID:The role of neurotensin in central nervous system pathophysiology: what is the evidence? 1686 41

The ventral tegmental area (VTA) is involved in reward-related behaviours and the actions of psychostimulant drugs. It is influenced by afferents expressing a variety of neurotransmitters and neuromodulators; the innervation containing neurotensin is among the densest of these. Intra-VTA neurotensin activates dopaminergic neurons and plays an important role in the development of behavioural sensitization to psychostimulant drugs and possibly in schizophrenia. Using gold-coupled wheatgerm agglutinin as retrograde tracer in combination with nonisotopic in situ hybridization for neurotensin mRNA or neurotensin antibodies after colchicine treatment, the present study was undertaken to demonstrate the neurotensinergic neurons projecting to the VTA and determine whether (and in which subpopulations) neurotensin expression is regulated in VTA-projecting neurons after administrations of the psychostimulant drug methamphetamine or the antipsychotic haloperidol. This study reveals the lateral preoptico-rostral lateral hypothalamic continuum and the medial preoptic area as main sources for the neurotensin afferents of the VTA. Fewer neurotensinergic, VTA-projecting neurons are situated in the dorsal raphe, pedunculopontine and laterodorsal tegmental nuclei, lateral hypothalamic area, ventral endopiriform area, lateral septum, accumbens shell, parabrachial nucleus and different parts of the extended amygdala. The number of neurotensinergic VTA-projecting neurons increased significantly only after methamphetamine administration and exclusively in the accumbens shell. It is concluded that the widespread neurotensinergic VTA-projecting neurons, situated in areas involved in different reward-related behaviours, are well suited to convey distinct reward information to the VTA. The up-regulation of neurotensin expression selectively in VTA-projecting neurons in the accumbens shell following methamphetamine administration may be an important factor in the development of behavioural sensitization.
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PMID:Neurotensin afferents of the ventral tegmental area in the rat: [1] re-examination of their origins and [2] responses to acute psychostimulant and antipsychotic drug administration. 1688 12

Neurotensin (NT) is a 13-amino acid neuropeptide found in the central nervous system and in the gastrointestinal tract. It is closely associated anatomically with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT agonists in the treatment of various neuropsychiatric disorders. However, NT is readily degraded by peptidases, so there is much interest in the development of stable NT agonists, that can be injected systemically, cross the blood-brain barrier (BBB), yet retains the pharmacological characteristics of native NT for therapeutic use in the treatment of diseases such as schizophrenia, Parkinson's disease and addiction.
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PMID:Bioactive analogs of neurotensin: focus on CNS effects. 1688 57


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