Neurotensin: role in psychiatric and neurological diseases

Neurotensin (NT), an endogenous brain-gut peptide, has a close anatomical and functional relationship with the mesocorticolimbic and neostriatal dopamine system. Dysregulation of NT neurotransmission in this system has been hypothesized to be involved in the pathogenesis of schizophrenia. Additionally, NT containing circuits have been demonstrated to mediate some of the mechanisms of action of antipsychotic drugs, as well as the rewarding and/or sensitizing properties of drugs of abuse. NT receptors have been suggested to be novel targets for the treatment of psychoses or drug addiction.     

Interactions between neurotensin and dopamine in the brain: an overview

Neurotensin (NT)-like immunoreactivity is found in high concentrations in many brain areas under important dopaminergic control, such as the nucleus accumbens and the substantia nigra and its receptors are also highly concentrated in the A-9 and A-10 regions. Neurotensin-induced behavioral actions after intracerebral injections bear many similarities with neuroleptics. Moreover, NT is able to modify dopamine metabolism in various brain regions. Finally, 6-hydroxydopamine (6-OHDA) lesions of A-9 and A-10 regions markedly decrease NT receptors in these areas and in the caudate-putamen. All together, these data strongly suggest that NT interacts with mesolimbic and nigrostriatal dopaminergic pathways in the brain.     

The electrophysiological actions of neurotensin in the central nervous system

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.     

Alterations in regional brain neurotensin concentrations produced by atypical antipsychotic drugs.

Classical antipsychotic drugs, such as haloperidol, have been shown to increase the concentrations of neurotensin (NT) selectively in the nucleus accumbens and caudate nucleus of the rat. Several novel, putative antipsychotic drugs have also been found to produce increases in NT content in one or both of these brain regions. The present study sought to compare the effects of chronic treatment with three clinically efficacious atypical antipsychotic drugs, sulpiride, rimcazole and remoxipride, on regional brain NT concentrations to those of haloperidol. The concentrations of NT in five discrete brain regions were determined by a sensitive and specific radioimmunoassay. As previously reported, haloperidol increased NT concentrations in both the nucleus accumbens and caudate nucleus. Sulpiride and rimcazole produced significant increases in the concentration of NT in the caudate. NT concentrations were unaltered in any brain region by remoxipride at either of the doses tested. These data provide additional evidence for specific increases in regional brain NT concentrations produced by antipsychotic drugs.     

Brain neurotensin, psychostimulants, and stress--emphasis on neuroanatomical substrates

Neurotensin (NT) is a peptide that is widely distributed throughout the brain. NT is involved in locomotion, reward, stress and pain modulation, and in the pathophysiology of drug addiction and depression. In its first part this review brings together relevant literature about the neuroanatomy of NT and its receptors. The second part focuses on functional-anatomical interactions between NT, the mesotelencephalic dopamine system and structures targeted by dopaminergic projections. Finally, recent data about the actions of NT in processes underlying behavioral sensitization to psychostimulant drugs and the involvement of NT in the regulation of the hypothalamo-pituitary-adrenal gland axis are considered.     

Bioenergetic and oxidative effects of free 3-nitrotyrosine in culture: selective vulnerability of dopaminergic neurons and increased sensitivity of non-dopaminergic neurons to dopamine oxidation

Protein bound and free 3-nitrotyrosine (3NT) levels are elevated in neurodegenerative diseases and have been used as evidence for peroxynitrite generation. Intrastriatal injection of free 3NT causes dopaminergic neuron injury and represents a new mouse model of Parkinson's disease (PD). We are investigating the nature of free 3NT neurotoxicity. In primary ventral midbrain cultures, free 3NT damaged dopaminergic neurons, while adjacent non-dopaminergic neurons were unaffected. Combined treatment with free 3NT and subtoxic amounts of dopamine caused extensive death of non-dopaminergic forebrain neurons in culture. Free 3NT alone directly inhibited mitochondrial complex I, decreased ATP, sensitized neurons to mitochondrial depolarization, and increased superoxide production. Subtoxic concentrations of rotenone (instead of free 3NT) caused similar results. Additionally, free 3NT and dopamine combined increased extraneuronal hydrogen peroxide and decreased intraneuronal glutathione levels more than dopamine alone. Oxidative and bioenergetic processes have been proposed to contribute to neurodegeneration in PD. As free 3NT is a compound that is increased in PD, damages dopamine neurons in vivo and in vitro and has detrimental effects on neuronal bioenergetics, it is possible that free 3NT is an endogenous contributing factor to neuronal loss, in addition to being a marker of oxidative and nitrative processes.     

Different Subcellular Localization of Neurotensin-Receptor and Neurotensin-Acceptor Sites in the Rat Brain Dopaminergic System

The subcellular localization of neurotensin-receptor sites (NT2 sites) and neurotensin-acceptor sites (NT1 sites) was studied in rat caudate-putamen by isopycnic centrifugation in sucrose density gradients. [3H]Neurotensin binding to NT2 sites occurred as a major peak at higher sucrose densities, colocalized with [3H]dopamine uptake, and as a small peak at a lower density; whereas binding to NT1 sites occurred as a single large peak at an intermediate density. 6-Hydroxydopamine lesions of the median forebrain bundle resulted in a total loss of NT2 sites in the caudate-putamen but did not affect NT2 sites in the nucleus accumbens and the olfactory tubercle. NT1 sites were not affected. Kainic acid injections into the rat caudate-putamen led to a partial decrease of NT1 sites in this region 5 days later. After a few weeks they returned to normal. Therefore NT2 sites are probably associated with presynaptic nigrostriatal dopaminergic terminals in the caudate-putamen but not in the nucleus accumbens and the olfactory tubercle. A possible association of NT1 sites with glial cells is suggested.     

Endogenous CNS Expression of Neurotensin and Neurotensin Receptors Is Altered during the Postpartum Period in Outbred Mice

Neurotensin (NT) is a neuropeptide identical in mice and humans that is produced and released in many CNS regions associated with maternal behavior. NT has been linked to aspects of maternal care and previous studies have indirectly suggested that endogenous NT signaling is altered in the postpartum period. In the present study, we directly examine whether NT and its receptors exhibit altered gene expression in maternal relative to virgin outbred mice using real time quantitative PCR (qPCR) across multiple brain regions. We also examine NT protein levels using anti-NT antibodies and immunohistochemistry in specific brain regions. In the medial preoptic area (MPOA), which is critical for maternal behaviors, mRNA of NT and NT receptor 3 (Sort1) were significantly up-regulated in postpartum mice compared to virgins. NT mRNA was also elevated in postpartum females in the bed nucleus of the stria terminalis dorsal. However, in the lateral septum, NT mRNA was down-regulated in postpartum females. In the paraventricular nucleus of the hypothalamus (PVN), Ntsr1 expression was down-regulated in postpartum females. Neurotensin receptor 2 (Ntsr2) expression was not altered in any brain region tested. In terms of protein expression, NT immunohistochemistry results indicated that NT labeling was elevated in the postpartum brain in the MPOA, lateral hypothalamus, and two subregions of PVN. Together, these findings indicate that endogenous changes occur in NT and its receptors across multiple brain regions, and these likely support the emergence of some maternal behaviors.     

Antipsychotic drugs increase N-acetylaspartate and N-acetylaspartylglutamate in SH-SY5Y human neuroblastoma cells

N -Acetylaspartate (NAA) and N -acetylaspartylglutamate (NAAG) are related neuronal metabolites associated with the diagnosis and treatment of schizophrenia. NAA is a valuable marker of neuronal viability in magnetic resonance spectroscopy, a technique which has consistently shown NAA levels to be modestly decreased in the brains of schizophrenia patients. However, there are conflicting reports on the changes in brain NAA levels after treatment with antipsychotic drugs, which exert their therapeutic effects in part by blocking dopamine D₂ receptors. NAAG is reported to be an agonist of the metabotropic glutamate 2/3 receptor, which is linked to neurotransmitter release modulation, including glutamate release. Alterations in NAAG metabolism have been implicated in the development of schizophrenia possibly via dysregulation of glutamate neurotransmission. In the present study we have used high performance liquid chromatography to determine the effects of the antipsychotic drugs haloperidol and clozapine on NAA and NAAG levels in SH-SY5Y human neuroblastoma cells, a model system used to test the responses of dopaminergic neurons in vitro . The results indicate that the antipsychotic drugs haloperidol and clozapine increase both NAA and NAAG levels in SH-SY5Y cells in a dose and time dependant manner, providing evidence that NAA and NAAG metabolism in neurons is responsive to antipsychotic drug treatment.     

Balance of glutamate and dopamine in the nucleus accumbens modulates self-stimulation behavior after injection of cholecystokinin and neurotensin in the rat brain.

Subpopulations of dopamine (DA) neurons in the ventral mesencephalon have been reported to contain cholecystokinin (CCK) and neurotensin (NT), giving rise to DA, DA/NT, NT/CCK and DA/CCK/NT projections. More precisely, colocalized DA/CCK neurons project mainly to the caudal part of the medial nucleus accumbens, whereas its rostral portion receives CCK and DA nerve terminal networks that are structurally independent. We investigated the respective effects of both CCK and NT on the intracranial self-stimulation behavior (ICSS) from the posterolateral hypothalamus after their direct administration into the lateral ventricle (ICV), into both portions of the nucleus accumbens, into the ventral tegmental area (VTA), and into the subiculum of the hippocampal formation (SUB). The ICV injection of 150 pmol CCK8 induced a decrease in the rate of ICSS. By contrast, the direct administration of 150 pmol CCK8 into the mediocaudal part of the nucleus accumbens induced an enhanced rate of ICSS while a similar injection into its rostral portion gave rise to a slight transient decrease of ICSS. When injected into the SUB, both CCK8 and glutamate produced decreased rates of ICSS at femtomolar doses one thousand-fold under the picomolar concentrations used for ICV injections. Neurotensin induced similar behavioral profiles to that observed after the ICV injection of CCK8 or into both portions of the nucleus accumbens. Neurotensin and CCK8 displayed opposite effects on ICSS when administered into the SUB or into the VTA, suggesting they may regulate ICSS most probably through different synaptic mechanisms and through different anatomical pathways.     

Neurotensin: dual roles in psychostimulant and antipsychotic drug responses

Central administration of neurotensin (NT) results in a variety of neurobehavioral effects which, depending upon the administration site, resemble the effects of antipsychotic drugs (APDs) and psychostimulants. All clinically effective APDs exhibit significant affinities for dopamine D(2) receptors, supporting the hypothesis that an increase in dopaminergic tone contributes to schizophrenic symptoms. Psychostimulants increase extracellular dopamine (DA) levels and chronics administration can produce psychotic symptoms over time. APDs and psychostimulants induce Fos and NT expression in distinct striatal subregions, suggesting that changes in gene expression underlie some of their effects. To gain insight into the functions of NT, we analyzed APD and psychostimulant induction of Fos in NT knockout mice and rats pretreated with the NT antagonist SR 48692. In both NT knockout mice and rats pretreated with SR 48692, haloperidol-induced Fos expression was markedly attenuated in the dorsolateral striatum; amphetamine-induced Fos expression was reduced in the medial striatum. These results indicate that NT is required for the activation of specific subpopulations of striatal neurons in distinct striatal subregions in response to both APDs and psychostimulants. This review integrates these new findings with previous evidence implicating NT in both APD and psychostimulant responses.     

Specific involvement of neurotensin type 1 receptor in the neurotensin-mediated in vivo dopamine efflux using knock-out mice

Abstract Neurotensin is a tridecapeptide neurotransmitter known to be involved in psychiatric disorders, various physiological processes and several different neurobiological mechanisms, including modulation of accumbal dopamine release. Two neurotensin extracellular binding sites, namely NT1- and NT2-receptor (NT1R and NT2R), have been cloned from the rat brain. These receptors are distinguishable by their different in vitro pharmacological properties but the available pharmacological tools have weak in vivo potency and specificity. The use of genetically engineered knock-out mice has provided a powerful alternative to the classical pharmacological approach to investigate their respective roles. In this study, using in vivo differential pulse amperometry, we show that, in wild-type mice, neurotensin application into the ventral tegmental area dose-dependently evokes dopamine efflux in the nucleus accumbens. This neurotensin-mediated efflux is dramatically decreased in mice lacking NT1R while it is unaffected in NT2R-deleted mice. This finding indicates that a large part of the dopamine efflux evoked by neurotensin in the nucleus accumbens of wild-type mice is mediated via NT1R present in the ventral tegmental area.     

Current topics: brain penetrating neurotensin analog

Neurotensin (NT) is a neuropeptide found in the central nervous system and gastrointestinal tract. It is closely associated with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT in various neuropsychiatric disorders. Because NT is readily degraded by peptidases, our group has developed various NT agonists that can be injected systemically, cross the blood brain barrier (BBB), yet retain the characteristics of native NT. The most widely studied and successful of these compounds, called NT69L, holds promise as a therapeutic agent for Parkinson's disease, schizophrenia, psychostimulant abuse and nicotine dependence, and serves as a tool to study the cellular and molecular effects of NT.     

The electrophysiological actions of dopamine and dopaminergic drugs on neurons of the substantia nigra pars compacta and ventral tegmental area.

The dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area play a crucial role in regulating movement and cognition respectively. Several lines of evidence suggest that a degeneration of dopaminergic cells in the substantia nigra produces the symptoms of Parkinson's disease. On the other hand, a hyperactivity of the dopaminergic transmission in the brain induces dyskinesia, dystonia and psychosis. It is also well established that the euphoric and rewarding responses evoked by drugs of addiction, such as amphetamine and cocaine, are mediated by central dopamine systems. Electrophysiological experiments which study the activity of single dopaminergic neurons in the ventral mesencephalon have shown that dopamine and dopaminergic drugs reduce the firing frequency of these cells. This is due to the stimulation of D2-D3 autoreceptors and to a hyperpolarization of the membrane produced by an increase in potassium conductance. In addition, substances which increase the release (amphetamine), the synthesis (levodopa) or block the uptake (cocaine, nomifensine, amineptine) of dopamine in the brain inhibit the firing activity of the dopaminergic cells throughout dopamine-mediated mechanisms. In this review, we will briefly examine the literature concerning the physiological and behavioural responses caused by dopamine and dopaminergic agents on the dopaminergic neurons of the ventral mesencephalon. Our conclusion suggests that the electrophysiological actions of dopamine and dopamine-related drugs on dopaminergic cells in the ventral mesencephalon might be indicative of the pharmacological effects of these agents on the brain.     

Hypothesis: A nicotine-dopamine interaction linking smoking with Parkinson's disease and tardive dyskinesia

1. Nicotine, an important pharmacological component of cigarette smoke, is known to have significant effects on central nervous system (CNS) dopaminergic function. Although acute doses of nicotine have been shown to facilitate dopamine release, recent data indicate that chronic nicotine treatment may actually decrease CNS dopamine turnover in the striatum. 2. A number of epidemiological investigations have demonstrated that individuals who are or who have been smokers are less likely to develop idiopathic Parkinson's disease (a disorder involving a deficit in nigrostriatal dopaminergic neurotransmission). In addition, there is preliminary evidence that individuals with tardive dyskinesia (a hyperkinetic movement disorder observed in some cases of chronic neuroleptic treatment and thought by some to be associated with striatal dopamine receptor supersensitivity) are more likely to be smokers. 3. A unitary hypothesis is presented, proposing that smoking in early adult life may decrease CNS catecholamine turnover, thereby protecting against free radical formation from catecholamine oxidation that in turn damages striatal neurons. These individuals are thereby "protected" from the later development of Parkinson's disease. In this hypothetical scheme, individuals who are given neuroleptics and who also are smokers may develop a greater degree of dopamine receptor supersensitivity due to combined receptor blockade by neuroleptics and a decrease in CNS dopamine turnover caused by nicotine, resulting in an increased prevalence of tardive dyskinesia in this group.     

A single exposure to novelty differentially affects the accumbal dopaminergic system of apomorphine-susceptible and apomorphine-unsusceptible rats

Individual differences in responses to mild, acute stressors in laboratory animals have commonly been observed in behavioural tests and at the level of hypothalamic-pituitary-adrenal axis responses. These differences are associated with dopamine transmission in the nucleus accumbens. Although the effect of mild stressors on dopamine transmission has been studied with microdialysis, it has not been studied at the level of the catecholaminergic network in the nucleus accumbens. In this study we have used microdialysis to measure extracellular concentrations of dopamine in vivo and immunocytochemistry for the enzyme tyrosine hydroxylase to assess the effect of a single exposure to novelty on the neurochemistry of the nucleus acc umbens in apomorphine-susceptible and apomorphine-unsusceptible rats. These rats are a valid animal model for studying individual differences in responses to environmental stressors and drugs of abuse. We demonstrated that a mild stressor like novelty increased the extracellular concentration of dopamine in the nucleus accumbens in apomorphine-susceptible rats to a larger and longer-lasting degree than in apomorphine-unsusceptible rats. Furthermore we demonstrated that novelty increased the tyrosine hydroxylase-immunoreactive fibre network in the nucleus accumbens shell of apomorphine-susceptible rats, which are rats that are particularly reactive to stressors, but not in the shell of apomorphine-unsusceptible rats, which are rats that are relatively stress-resistant. In conclusion, we have shown that the accumbal dopaminergic system of apomorphine-susceptible rats is more sensitive to an environmental stressor than that of apomorphine-unsusceptible rats. Combined with the fact that these animals also differ in their sensitivity to drugs of abuse, which are known to affect the dopaminergic system, these data provide a solid basis for further studying the differences in the dopaminergic responsiveness to drugs of abuse between apomorphine-susceptible and apomorphine-unsusceptible rats.     

Bioactive analogs of neurotensin: focus on CNS effects

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.     

Different roles of intrahypothalamic and nigrostriatal dopaminergic systems in thermoregulatory responses of the rat

Classically, two neurotransmitters in the brain have been implicated in thermoregulation: 5-hydroxytryptamine and norepinephrine. A dopamine action is less well-known and usually has been studied by means of pharmacological rather than physiological procedures. In the present work using a physiological approach to the problem, the role of different central dopaminergic systems in the thermoregulatory response of rats exposed to cold (4 degrees C) or warm (45 degrees C) environments has been studied. Rostral incertohypothalamic neurons in the medial preoptic area synthesized and released more dopamine in response to a warm but not to a cold environment. On the other hand DA and DOPAC levels in nigrostriatal systems were decreased by cold but not warm environments. The dopaminergic neurons projecting to nucleus accumbens or hypothalamus do not appear to be related to the thermoregulatory response in the rat.     

多巴胺调节海马神经元可塑性的研究进展

多巴胺是脑内重要的信息传递物质,不仅可以作为递质释放到前额叶、伏隔核等脑区,直接进行信息传递,也可以作为调质调节其它突触递质的传递,并影响神经元可塑性。海马参与构成边缘系统,受多巴胺能神经支配,执行着有关学习记忆以及空间定位的功能。海马神经元的可塑性是学习记忆的细胞分子基础。研究表明,多巴胺对海马神经元的突触可塑性和兴奋性可塑性都具有重要的调节作用。本文扼要综述多巴胺对海马神经元突触可塑性和兴奋性可塑性的调节机制的研究进展,以期为DA系统参与海马区学习记忆功能的研究提供新思路,更深入地了解学习记忆的神经机制。