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 tridecapeptide which fulfills many of the requisite criteria for a role as a central nervous system (CNS) neurotransmitter. It is closely associated with CNS dopamine neurons and has been shown to interact with dopamine at physiological, anatomical and behavioral levels. Neurotensin is colocalized with dopaminergic neurons in the hypothalamus and midbrain. In addition, it blocks behaviors associated with activation of the dopaminergic pathways. Centrally administered NT has been shown to mimic many of the actions of antipsychotic drugs. In addition, the concentration of NT in cerebrospinal fluid is decreased in patients with schizophrenia. Administration of clinically effective antipsychotic drugs increases concentrations of NT in the caudate nucleus and nucleus accumbens. NT has been shown to play a role in signal transduction by mostly mobilizing calcium stores following inositol phosphate formation. This has been linked to subsequent events in protein phosphorylation. Lipophilic NT receptor agonists may represent a novel approach to the development of a new class of antipsychotic drugs.
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PMID:The neurobiology of neurotensin: focus on neurotensin-dopamine interactions. 166 85

Despite the considerable data generated thus far, a unifying theory for the role(s) of NT in the CNS has not been achieved. However, several conclusions with clinical relevance can be made about neurotensin. First, NT is intimately associated with the mesolimbic DA system and has the ability to selectively modulate this system. Second, NT possesses a pharmacobehavioral profile that is similar to antipsychotic drugs, with many similarities to the atypical class of antipsychotics drugs. If the pathogenesis of schizophrenia is related to dopaminergic hyperactivity, then the existence of an endogenous NT system that modulates the activity of the DA system, may represent a mechanism for the prevention of psychosis. The ability of the atypical antipsychotic drugs to effectively reduce the symptoms of schizophrenia does not depend entirely upon the blockade of D2 receptors, yet many of these drugs alter NT concentrations. The development of NT receptor agonists that can cross the blood brain barrier may prove valuable in the treatment of schizophrenia, while avoiding the liability of EPS and TD.
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PMID:Neurotensin-dopamine interactions: relevance to schizophrenia and the action of antipsychotic drugs. 167 73

The endogenous neuropeptide, neurotensin (NT) alters the firing frequencies of certain neurons in the central nervous system (CNS). This is one of the findings that support the hypothesis that NT is a neurotransmitter substance. The direct application of NT on CNS neurons causes predominantly excitatory effects. These effects occur in a dose-related fashion via a calcium-dependent postsynaptic mechanism. The C-terminal hexapeptide fragment, NT 8-13 exerts similar electrophysiological effects to NT, while the N-terminal octapeptide fragment, NT 1-8 is devoid of such activity. NT produces a significant increase in the firing rates of individual neurons in the substantia nigra (SN), ventral tegmental area (VTA), medial prefrontal cortex (MPF), hypothalamus, and periaqueductal grey (PAG). This excitation occurs with a rapid onset and is readily reversible after cessation of NT application. In contrast, NT has no effect or weak inhibitory effects on the firing rates of neurons in the locus coeruleus (LC) and cerebellum. These electrophysiological actions of NT appear to be unique and not shared by other neurotransmitter and neuropeptide receptor antagonists and agonists that have been studied via direct co-application. NT attenuates dopamine (DA)-induced inhibition associated with direct application onto neurons in the SN and VTA both in vivo and in vitro. Intracellular recordings suggest that direct application of higher concentrations of NT appears to produce 'depolarization block' on individual neurons in the SN, VTA, MPF, and hypothalamus. The electrophysiological consequences of NT application not only show similarities to clinically efficacious antipsychotic medications, but also demonstrate the ability of NT to modulate the activity of dopamine (DA) neurons at the cellular level via specific NT binding sites. These findings further underscore the possibility that NT may play a pre-eminent role in the pathogenesis of, and psychopharmacological management of neurological and psychiatric disorders purportedly related to perturbation of CNS DA systems including schizophrenia.
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PMID:The electrophysiological actions of neurotensin in the central nervous system. 189 Sep 28

Thirty years ago, dopamine was identified as an essential neurotransmittor. Since then, it has been the most written about CNS molecule. Considerable evidence implicates disturbances of brain dopamine function in the pathophysiology of several psychiatric and neurologic disorders, especially schizophrenia and Parkinson's disease. In the last decade, there have been important advances in the understanding of the diversity of CNS dopamine neurons and the chemical basis of this diversity, which relies upon molecular physiology of D1 and D2 receptors. Heterogeneity is remarkable at different levels, anatomical, biochemical, morphological or functional; besides, region specific interactions with other neurotransmittors and sometimes colocalisation of dopamine with cholecystokinin and/or neurotensin suggest the integration of dopamine neurons in functional subunits.
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PMID:[The mesencephalic dopaminergic system. Implications for neuroleptic treatment]. 197 42

Previous studies have focused on the role of the central nucleus of the amygdala (CeA) in cardiovascular and other amygdaloid functions. The combined retrograde tracing/immunohistochemical method was used to test for the presence of enkephalin, neurotensin, neuropeptide Y, and catecholamine neurons within the nucleus of the solitary tract that send efferents to the CeA. After injections of retrograde tracer into the CeA, retrogradely labeled neurons were observed within the caudal, medial nucleus of the solitary tract. Most CeA-projecting neurons were located ipsilaterally within the medial nucleus of the solitary tract at the level of the area postrema. Retrogradely labeled enkephalin- and neurotensin-immunoreactive neurons were found within the medial nucleus of the solitary tract at this level, while retrogradely labeled neuropeptide Y-immunoreactive neurons were found within the medial nucleus of the solitary tract rostral to the area postrema. About 60-74% of CeA-projecting cells were also immunoreactive for tyrosine hydroxylase. Approximately 9% of retrogradely neurons were phenylethanolamine-N-methyltransferase immunoreactive. The results provide evidence that within the nucleus of the solitary tract, peptidergic CeA-projecting neurons have a topographic distribution. In addition, noradrenergic neurons within the A2 group, rather than adrenergic neurons of the C2 group, provide the bulk of catecholaminergic input to the CeA from the nucleus of the solitary tract. Cell counts indicate that each of these peptides may be colocalized (to varying extents) within catecholamine-producing neurons. Also the catecholaminergic and enkephalinergic contribution to the ascending pathway from the nucleus of the solitary tract to the CeA distinguishes it neurochemically from the descending pathway. Thus, although there are afferent and efferent connections between the nucleus of the solitary tract and CeA, their peptidergic/neurotransmitter connections are not necessarily reciprocal. Input from nucleus of the solitary tract peptidergic and catecholaminergic neurons to the CeA may be important in the etiology of a number of pathophysiological conditions including hypertension, gastric ulcers, and schizophrenia.
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PMID:Organization of peptidergic and catecholaminergic efferents from the nucleus of the solitary tract to the rat amygdala. 198 Nov 74

Evidence has accumulated to implicate neuropeptides localized within midbrain dopamine neurons (cholecystokinin, neurotensin, acetylcholinesterase) in synaptic transmission, mental disease, and pharmacotherapy. We suggest a means by which antipsychotic drugs alter the dynamics between dopamine and colocalized peptides: the intrinsic ability of these agents to stimulate dopamine neuronal activity while blocking dopamine receptors modulates the ratio of catecholaminergic to peptidergic transmission within the mesotelencephalic system. Imbalances of peptide and dopamine cotransmission and their modulation by neuroleptics may be relevant to the pathogenesis and pharmacotherapy of schizophrenia.
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PMID:A mechanism for the involvement of colocalized neuropeptides in the actions of antipsychotic drugs. 256 35

Neurotensin (NT) concentrations in cerebrospinal fluid (CSF) were measured by a sensitive and specific radioimmunoassay in psychiatric patients and age- and sex-matched normal controls. No increase in CSF NT concentrations was observed after antipsychotic drug treatment. CSF NT concentrations were significantly lower in one group of schizophrenic subjects. NT concentrations were unaltered in patients with depression, anorexia/bulimia, or premenstrual syndrome, and no rostral-caudal gradient for NT in CSF was evident. NT concentrations were not related to age or sex, and probenecid treatment did not alter CSF NT concentrations. Finally CSF NT concentrations were unaltered in paranoid schizophrenic subjects. These findings confirm and extend previous studies of CSF NT that showed certain patients with schizophrenia, nonparanoid type, have reduced CSF concentrations of this tridecapeptide.
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PMID:Neurotensin-like immunoreactivity in cerebrospinal fluid of patients with schizophrenia, depression, anorexia nervosa-bulimia, and premenstrual syndrome. 257 18

The long-term administration of neuroleptics causes tardive dyskinesia, which closely resembles levodopa-induced dyskinesias, and is brought about through complex mechanisms which are ill-defined. It is generally believed that the pathogenesis of tardive dyskinesia relates closely to the chronic blockade of dopamine receptor sites and that its pathophysiology results from a hypersensitivity of dopamine receptor sites. In the therapeutic management of neuroleptic-induced tardive dyskinesia, in addition to reserpine and lithium, diazepam, baclofen, or gamma-vinyl-gamma-aminobutyric acid have also been advocated. However, the reported beneficial effects of diazepam and GABA-mimetic agents in ameliorating the symptoms of tardive dyskinesia may occur through a mechanism which does not necessarily link transmission involving both dopamine and GABA. The presence of high concentrations of both cholecystokinin and opioids in the striatum also suggests that these peptides not only may influence dopaminergic transmission, but that they may also be relevant to the psychopathology of schizophrenia and to the therapeutic effects of neuroleptics. Indeed, the acute and chronic administration of neuroleptics alters the levels of cholecystokinin and opioids and their receptors in several brain regions including the striatum. However, neuroleptics also alter the biochemical integrity of neurotensin, neuropeptide Y, substance P and somatostatin, which may also play a role in the overall expression of the neuroleptic-induced extrapyramidal reactions.
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PMID:Dopamine, GABA, cholecystokinin and opioids in neuroleptic-induced tardive dyskinesia. 290 20

In the past twenty years, more than thirty peptides have been discovered to be present in the mammalian central nervous system (CNS). As the neuroanatomical distribution, neurochemical, electrophysiological and pharmacobehavioral effects of this novel group of neuroregulators have been described, it is evident that certain of these peptide-containing neural circuits may be pathologically altered in neuropsychiatric disorders. Although much attention has been focused on the opioid peptides, substantial data strongly support the hypothesis that non-opioid peptides such as somatostatin, neurotensin and substance P are altered in a diverse number of neuropsychiatric disorders including Alzheimer's disease, Huntington's chorea, Parkinson's disease, major depression and schizophrenia.
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PMID:Involvement of non-opioid peptides in the pathogenesis of neurological and psychiatric disorders: evidence from CSF and post-mortem studies. 293 45

In mammalian brain, dopaminergic (DA) cell bodies located in the ventral mesencephalon give rise to meso-cortical, meso-limbic and meso-striatal systems. Among these, the meso-cortical DA pathway is particularly involved in the processing of emotional and cognitive responses. We demonstrate that the rat meso-cortical neurons specifically contain, in addition to DA, another transmitter, Neurotensin. If this co-localization exists in man, it may provide an anatomical substratum for the biological theory of schizophrenia as well as an indication that potential anti-psychotic drugs which act differentially on the DA ascending transmissions can be developed.
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PMID:Extensive co-localization of neurotensin with dopamine in rat meso-cortico-frontal dopaminergic neurons. 313 72


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