Next Article in Journal
Street Choice Logit Model for Visitors in Shopping Districts
Next Article in Special Issue
Working Memory Training in Schizophrenia and Healthy Populations
Previous Article in Journal
Cultural Adaptations of Prolonged Exposure Therapy for Treatment and Prevention of Posttraumatic Stress Disorder in African Americans
Previous Article in Special Issue
Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization
Open AccessReview

Elucidating the Role of Neurotensin in the Pathophysiology and Management of Major Mental Disorders

Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research, Mayo Clinic, Jacksonville FL 32224, USA
Department of Psychiatry, University of Florida, Gainesville FL 32611, USA
Author to whom correspondence should be addressed.
Behav. Sci. 2014, 4(2), 125-153;
Received: 6 March 2014 / Revised: 15 May 2014 / Accepted: 21 May 2014 / Published: 13 June 2014
(This article belongs to the Special Issue Management and Treatment of the Major Mental Disorders)


Neurotensin (NT) is a neuropeptide that is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various mental disorders. This review outlines data implicating NT in the pathophysiology and management of major mental disorders such as schizophrenia, drug addiction, and autism. The data suggest that NT receptor analogs have the potential to be used as novel therapeutic agents acting through modulation of neurotransmitter systems dys-regulated in these disorders.
Keywords: neurotensin; schizophrenia; antipsychotic drugs; addiction; autism spectrum disorder; animal models neurotensin; schizophrenia; antipsychotic drugs; addiction; autism spectrum disorder; animal models

1. Introduction

Neurotensin (NT) is a neuropeptide that was originally isolated from bovine hypothalami [1]. In addition to its presence in the central nervous system (CNS), it is also found in the gastrointestinal tract, and the cardiovascular system. Both the central and peripheral effects of NT are mediated through the activation of NT receptors. There are three well-characterized NT receptors, NTS1, NTS2 and NTS3 [2,3]. NTS1 and NTS2 are G-protein-coupled receptors with seven-transmembrane domains and are distinguished based on their sensitivity to the histamine receptor antagonist, levocabastine [4,5,6,7], with NTS1 being insensitive to this drug. NTS2 has lower affinity to NT and is sensitive to levocabastine.
Functionally, NTS1 is coupled to the phospholipase C and the inositol phosphate (IP) signaling cascade (refer to [2,8] for reviews). NTS1 signaling can also be mediated through activation of cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), arachidonic acid production, and mitogen-activated protein (MAP) kinase phosphorylation [9,10,11,12,13,14,15,16]. The signaling properties of NTS2 are controversial depending upon the species from which the NTS2 was isolated and the cell system used to evaluate signaling [17,18]. NTS3/sortilin is a single transmembrane receptor domain [3,19] that modulates NT intracellular sorting and signaling processes [19] and has been associated with IP and MAP pathways in glial cells [20].
NT’s role has been explored in several physiological and pathological conditions including pain, central control of blood pressure, eating disorders, cancer, inflammation, and CNS disorders [21,22], This review will address the potential role of NT in the management of major mental disorders with special focus on schizophrenia, substance abuse, and autism.

2. Neurotensin and Schizophrenia

2.1. Overview

Schizophrenia is a severe psychiatric disorder that afflicts approximately 1% of the population worldwide. It begins in late adolescence or early adulthood and usually continues throughout life. Schizophrenia has varied symptoms including auditory hallucinations and delusions (positive symptoms), inability to care for self, apathy and flattening affect, loss of sense of pleasure, and social withdrawal (negative symptoms). Schizophrenic patients also suffer from cognitive impairment including disturbances in attention, disorganization of thought and speech [23], and depression and social isolation [24]. Because of the wide range of symptoms, patients with schizophrenia have difficulty holding a job or caring for themselves, placing a significant burden on their families and society. Additionally, they experience a 20% shorter life span than the general population and are at an increased risk for committing suicide [25].
The pathophysiology of schizophrenia is not quite understood. Several hypotheses have been published, the most supported of which is the dopamine hypothesis [26,27]. While originally hyperdopaminergia was emphasized as the cause of schizophrenia [28] an imbalance of dopamine between different brain regions has been since accepted as causative factor in the pathophysiology of schizophrenia [29]. Hyperactivity of the mesolimbic dopamine system has been related to positive symptoms while hypo-activity of the mesocortical dopamine system has been proposed to cause the negative symptoms and cognitive impairment [29,30,31].
More recently the physiology of this disorder has expanded beyond dopamine dysfunction to include the glutamate, serotonin, and nicotinic/acetylcholine systems. The glutamate receptors including the ionotropic N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate (mGlu) receptors are also co-localized in many areas of the brain that are highly implicated in schizophrenia, such as hippocampus, striatum, and neocortex [32,33,34]. Therefore, disruptions in the glutamatergic circuitry have been hypothesized to play a role in the pathophysiology of the disease [35,36]. These disruptions are thought to be caused by reduced NMDA function on GABAergic neurons in subcortical regions [37]. The glutamatergic hypothesis has been supported by the following: (1) NMDA receptor antagonists precipitate positive, negative, and cognitive schizophrenia-like symptoms in humans and animals [38,39] and exacerbate symptoms of schizophrenia in patients with the disease [40]; (2) the genetic deletion of mGluR5 in mice results in decreased sensorimotor gating, decreased short-term spatial memory, and decreased sensitivity to locomotor deficits induced by NMDA receptor antagonists [41,42,43]. These behaviors are similar to those induced by glutamate hypo-function and are observed in the schizophrenic phenotype [44]; (3) treating rats with mGlu receptor selective negative allosteric modulators results in social interaction deficits, impaired working memory, reduced instrumental learning, and intensification of the effects of NMDA receptor antagonists [33,45,46,47,48]. Additionally, glutamate has been linked to a myriad of processes surrounding cognition, memory and perception [49]. These studies have led to targeting the major excitatory neurotransmitter in the brain, glutamate, as an emerging novel approach for the treatment of schizophrenia. However, clinical trials of drugs targeting glutamate receptors in schizophrenic patients have yet to provide convincing support for this hypothesis, as discussed further below.

2.2. Antipsychotic Drugs (APDs)

Although schizophrenia has been attributed to an imbalance in dopamine, recent reports implicate several interacting systems including the dopaminergic [50], serotonergic, glutamatergic, cholinergic, and GABAergic systems. Nonetheless, most of the currently available APDs mainly target the dopamine D2 receptors [51] or the serotonergic receptors [52,53,54]
The first generation, or “typical”, APDs derive their therapeutic ability mainly through antagonizing the high affinity dopamine D2 receptors [55]. Typical APDs are effective at reducing the frequency and severity of psychotic episodes, [56]; however, they fail to eliminate positive symptoms of schizophrenia and in most cases have little effect on the negative and cognitive symptoms, (e.g., [57]) Moreover, typical APDs carry a substantial risk for producing extrapyramidal, cardiovascular, and endocrine side effects [58].
The second generation, or atypical, APDs are characterized by their relative high-affinity for the serotonin 5-HT2A receptor. They are called “atypical”, because they have a low propensity to cause the motor side effects that are typical of the first generation compounds. 5-HT2A antagonism is thought to mitigate the adverse effects of striatal dopamine D2 antagonism. It is suggested that a higher ratio of a drug’s affinity for 5-HT2A receptors relative to dopamine D2 receptors can predict “atypicality”, indicatinglower risk of extrapyramidal side effects [59] and potential improvement in cognition as compared to typical APDs (refer to [60] for review). However, atypical APDs carry a risk of adverse effects including metabolic syndrome, obesity, sedation, and cardiovascular abnormalities [61]. Agranulocytosis, a potentially fatal condition marked by severely low white blood cell count, has restricted the use of clozapine.
The therapeutic importance of the effects of currently available APDs on dopaminergic neurotransmission is well established. On the other hand, clinical studies with drugs targeting glutamatergic neurotransmission as a mechanism of action of novel APDs are limited and controversial, althoughsuch drugs have shown potential as novel compounds to treat schizophrenia [62]. In one clinical study, patients treated with a metabotropic glutamate receptor agonists showed significant improvement in both positive and negative symptoms [63]. However, these results could not be replicated by Eli Lilly and Company, 2009. Interestingly, chronic administration of clozapine to mGluR5 knockout mice reverses sensorimotor gating deficits, ameliorates hyperactivity but does not improve memory deficits [64]. While a recent study shows that acute, subchronic and chronic treatment with haloperidol and olanzapine do not influence mGluR5 binding density [65], others [66] reported an increase in mGluR5 mRNA expression by haloperidol and sertindole. It is worth noting, though, that mRNA levels do not correlate with protein expression [67] and that APD treatment might affect mGlu receptor function [68]. The effects of APDs on mGlu receptors might also be due to a direct or an indirect interaction with dopamine D2 receptors [69].
Another approach targeting glutamate receptors involves allosterically activating NMDA receptors by targeting their glycine site. This can be achieved with glycine or its analogs or with drugs that inhibit glycine reuptake (glycine transport blockers). Antagonists of glycine transport have also been proposed to have therapeutic potential in treating schizophrenia [70,71]. Glycine transporter 1 (glycine T1) inhibitors have been used adjunctively with APDs to increase their efficacy in treating negative symptoms of schizophrenia [72,73,74]. In addition, clozapine blocks glycine transport and this mechanism may account for its reported advantage over other atypical APDs [75]. Similarly, studies with bioptertin, a non-amino acid derivative of glycine, yielded encouraging findings in decreasing negative symptoms with no major issues of tolerability or toxicity [76]. Thus, the inhibition of the glycineT1 or activation of the glutamate receptors (mGlu5, mGlu2 or mGlu3) might act towards normalizing the disruption of the aberrant signaling in these circuits in schizophrenic patients [77].
While the current APDs have profoundly impacted acute treatment of schizophrenia enormous challenges remain for long-term treatment. The long-term use of typical APDs is associated with the induction of extrapyramidal side effects and the benefits of atypical APDs are tempered by weight gain, metabolic changes, sexual dysfunction, and QTc-prolongation. This leads many patients to non-compliance and discontinuation of treatment [78]. Therefore, there is still a need for therapeutic agents mediating effects through novel targets that provide more effective treatment for schizophrenia with fewer side effects. Evidence suggests that targeting the NT system may provide a novel and promising treatment for schizophrenia.

2.3. Neurotensin and Dopaminergic Neurotransmission

NT co-localizes with and modulates the mesolimbic dopaminergic system with more than 80% of dopaminergic neurons expressing NTS1 [79,80,81]. The modulatory effect of NT on dopaminergic neurotransmission depends on the localization of the receptors [82], the threshold of the dopaminergic neurons for NT-induced depolarization [83,84], the amount of NT administered and the site of administration (for a comprehensive review, please refer to [85]).
In the nucleus accumbens (NA), NT receptors are co-localized with presynaptic and postsynaptic dopamine receptors. Pre-synaptically, NT inhibits dopamine D2 autoreceptors resulting in an antagonistic effect on dopamine D2 receptors and an increased firing of dopaminergic neurons via NTS1-mediated increase in intracellular Ca2+ [17,86]. On the other hand, post-synaptically NT causes a decrease in dopamine signal transduction in the same area [87]. However, in the dorsal striatum, NT receptors are located almost exclusively on presynaptic dopaminergic terminals causing dopamine D2 autoreceptor inhibition and increasing dopamine signaling [88].
NT also regulates the function of dopamine receptors. NT decreases the binding affinity of dopamine D2 receptors for its agonists [89,90]; up-regulates tyrosine hydroxylase gene expression [91,92]; and alters receptor-dependent second messenger systems, such as phosphorylation and de-phosphorylation equilibrium ([89] for review). At a plasma membrane level, NT also allosterically affects the function capacity of dopamine D2 receptor heterodimers [93].

2.4. Neurotensin and Glutamatergic Neurotransmission

The antipsychotic-like effect of NT in animal models has been attributed partially to the increase in the ventral striato-pallidal γ-aminobutyric acid (GABA) transmission. In turn, this causes a restoration of the glutamate levels in the medio-dorsal thalamic nucleus to the prefrontal cortex pathway, which seems to be reduced in patients with schizophrenia [94,95,96].
Intra-cortical perfusion with NT changes extracellular glutamate levels in a bell-shaped and concentration dependent manner indicating that NT plays a relevant role in the regulation of cortical glutamate neurotransmission [97]. Similar in vivo and in vitro studies indicate the enhancing effects of NT on endogenous glutamate [98,99,100,101,102]. The perfusion of NT in the NA is thought to activate NTS1 receptors located on accumbal glutamate terminals, thereby inducing an enhancement of glutamate outflow that could be associated with a concomitant and significant reduction in accumbal dopamine release [103].

2.5. Neurotensin and APDs

APDs affect NT circuits in brain regions that are involved in the pathophysiology of schizophrenia. Acute and chronic administration of APDs increases NT mRNA expression, NT peptide concentration, and NT release in the NA and caudate nucleus [104,105,106,107,108] (Table 1).
Table 1. Effects of APDs on the neurotensinergic system.
Table 1. Effects of APDs on the neurotensinergic system.
EffectTypical APDAtypical APD
mRNA expression↑ NT mRNA in DL striatum & NA [104,106,109]NT mRNA in NA [106,109]
↑ NT mRNA in neostriatum [107]
↑NT mRNA in SN/VTA [110]No change in SN/VTA [110]
NT receptor binding↑ NTR binding in SN [104]↓ NTR binding in SN & NA [104]
↑ receptor density [111]↓ receptor density [111]
NT release↑ NT release in NA & striatum [112]↑ NT release in NA [112]
NT tissue concentration↑ NT levels in NA & caudate [104,105,113,114,115,116,117]↑ NT levels in caudate [114]
↑ NT-IR in NA [118,119]
↑ NT-IR in striatum [120]↑ NT-IR in Vstriatum & mPFC [120]
DL Striatum = dorso-lateral striatum; NA = nucleus accumbens; NTR = neurotensin receptor; SN = substantia nigra; VTA = ventral tegmental area; NT-IR = neurotensin immune-reactivity; V striatum = ventral striatum; mPFC = medial prefrontal cortex; ↑ = increase; ↓ = decrease.
In addition to the biochemical interaction between NT and APDs, central administration of NT mimics behaviors observed after peripheral administration of APDs. Both induce hypothermia, analgesia, and spontaneous hypo-activity [121,122,123]. NT also reproduces the behavioral response of APD in animals used to evaluate these drugs’ actions [124], such as blockade of apomorphine-induced climbing and physostigmine-induced yawning [125,126], increased vacuous chewing movements [127], decreased avoidance behavior [128], and reversal of drug-induced disruption of prepulse inhibition (PPI) of the acoustic startle response [129]. The PPI of the acoustic startle reflex is defined as a decrease in the startle reflex induced by a strong acoustic stimulus when preceded by a weak prepulse. It measures pre-attentive sensorimotor gating (for review see [130]). These results strengthen the hypothesis that NT acts as an endogenous APD [131].

2.6. Neurotensin Analogs in Animal Models of Psychosis

Because of the close association of NT with dopaminergic neurons, NT’s neuro-modulatory effects on the dopaminergic system, and data to suggest that APDs act through their effects on endogenous NT [132], this peptide has been hypothesized to be of therapeutic value in the treatment of schizophrenia. Since NT is rapidly degraded by peptidases when administered peripherally many laboratories, including ours, have been developing NT analogs that are resistant to peptidase degradation. These analogs have been used to elucidate the therapeutic efficacy of NT in animal models of schizophrenia. Most of these peptides are NT (8–13) analogs and are 6-amino acids in length. NT and its analogs show efficacy in several animal models of psychosis (Table 2).
Table 2. Animal behavioral studies implicating NT in the treatment of schizophrenia.
Table 2. Animal behavioral studies implicating NT in the treatment of schizophrenia.
Blockade of apomorphine-induced climbing[125,126,133]
Increase in vacuous chewing movement[127]
Reversal of drug-induced disruption of PPI[129,134,135,136,137,138,139,140,141,142]
Decrease conditioned avoidance behavior[143]
Enhance latent inhibition[144,145]
Attenuate amphetamine-induced activity[146]
PPI = prepulse inhibition.
NT analogs inhibit stereotyped apomorphine-induced climbing without affecting sniffing and licking [133,147,148]. NT analogs block amphetamine- and phencyclidine (PCP)-induced hyperactivity [146,148,149], a condition that may reflect both positive and negative symptoms of schizophrenia [40,150]. The NT agonist, NT69L, which is nonselective for NTS1 and NTS2, also attenuates the PCP-induced increase in glutamate in the prefrontal cortex of the rat [149]. Additionally, NT analogs block amphetamine-, dizocilpine-, and DOI-induced disruption in PPI [134,135,136,148,151]. These compounds affect catecholamine, glutamate, and serotonin (5-HT2A) receptors, respectively. These peptides also inhibit conditioned avoidance responding, which is a test with high predictive validity for screening for APDs in rats [152]. The effect of the individual NT analogs in animal models used for screening APDs has been recently reviewed [22].
The use of NT receptor subtype 1 and 2 knockout mice (NTS1−/− and NTS2−/−) provided further evidence for the involvement of NT in the pathophysiology of schizophrenia. NTS1−/− mice show higher basal locomotor activity, greater sensitivity to amphetamine-induced hyperactivity, higher mobility in forced swim test and tail suspension test [153,154] and diminished PPI [137]. Conversely, others [138] detected no difference in basal or amphetamine-induced PPI between NTS1−/− and wild type mice and showed an increase in basal PPI in NTS2−/− mice. Biochemically, NTS1−/− mice are hyper-dopaminergic in a way that is similar to the excessive striatal dopamine activity reported in schizophrenia and have lower basal glutamate levels. In addition, mRNA and protein for dopamine D1 and D2 receptors and glutamate NMDA2A receptor subunits are down-regulated in NTS1−/− suggesting possible interactions between NT, dopamine, and glutamate in the prefrontal cortex [155]. The results show promise for the use of NTS−/− mice as a model for schizophrenia.

2.7. Neurotensin Levels in Patients with Schizophrenia

Clinical studies in patients with schizophrenia support the hypotheses generated from animal studies with regard to NT. Drug-free schizophrenic patients have reduced cerebrospinal fluid (CSF) NT concentrations [156,157,158,159,160] which appear to be correlated with more severe psychopathology [156,157,159,161]. Effective treatment with APDs normalizes CSF NT concentrations in a subgroup of schizophrenic patients with lower CSF NT [157,159,160,161]. Additionally, this increase in CSF NT concentration is positively correlated with improvement of negative symptoms [159,161]. However, examination of the NT system in human postmortem tissue has produced inconsistent results ([87,162] for review) (Table 3).
Table 3. Human studies implicating NT in the pathophysiology of schizophrenia.
Table 3. Human studies implicating NT in the pathophysiology of schizophrenia.
↓ CSF NT levels in drug free schizophrenic patients[156,157,158,159,160]
↓ in CSF NT levels correlated with severe psychopathology[161]
↑ CSF NT levels positively correlated with improving negative symptoms of schizophrenia[159,161]
↑ = increase; ↓ = decrease.

2.8. Potential Side Effects of NT Analogs

NT analogs with higher selectivity to NTS1 cause transient hypothermia and hypotension (refer to [22] for review).
In summary, the data suggest that NT neurotransmission plays a role in the pathophysiology of schizophrenia and the mechanism of action of APDs. Additionally, animal studies provide rationale for pursuing the development of NT analogs as novel therapeutic approaches for the treatment of schizophrenia. Such use of NT analogs may also have other benefits, which include: (1) attenuating smoking (please see section on NT and substance abuse) that is prevalent in schizophrenic patients [163]; (2) being weight neutral, unlike most atypical APDs, which cause weight gain. Indeed weight loss may occur [164,165,166]; and (3) having no motor extrapyramidal side effects as is seen with typical APDs [133] as NT does not only affect dopamine but also modulates several neurotransmitter systems similar to the effects of atypical APDs.

3. Neurotensin and Substance Abuse

3.1. Overview

The cycle of addiction involving acquisition, maintenance, withdrawal, and relapse is associated with persistent changes in the brain, particularly the mesocorticolimbic dopamine system (the reward pathway). This circuit projects from the ventral tegmental area (VTA) to the NA, olfactory tubercle, frontal cortex, and amygdala [167]. NT, because it is co-localized with dopamine neurons and modulates dopamine transmission, is a candidate for a regulatory role in reward and addiction [87]. This review will focus on NT’s involvement in addiction to psychostimulant drugs, nicotine and alcohol [168,169,170].

3.2. Neurotensin and Psychostimulants

Psychostimulant drugs include cocaine, amphetamine, methamphetamine, methylphenidate, and nicotine. Behavioral sensitization, an animal model for addiction to this class of drugs [171,172], is a process by which the same dose of drug produces increasing degrees of locomotor effects with repeated administration [173]. Locomotor sensitization depends on activation of the mesolimbic dopamine system with additional long-term influences on glutamate, GABA, k-opioid, and other neurotransmitter systems [174]. Initiation of sensitization is associated with changes in the NA shell, while maintenance of sensitization involves the NA core [175,176]. NT’s effects on reward pathways depend on site of action. For example, when injected into the VTA, NT produces hyperactivity and dopamine release in the NA, similarly to effects of psychostimulants [177]. In contrast, NT applied directly to the NA reduces the response to psychostimulants, similarly to that of brain-penetrating NT analogs given extracranially [178].

3.3. Nicotine

The NT analog NT69L blocks initiation and sensitization to nicotine [179,180], consistent with an antagonism of nicotine’s psychostimulant effects. In a study of nicotine self-administration, rats were treated with either NT69L or saline once they achieved a stable level of responding to nicotine. Pretreatment with NT69L attenuated nicotine self-infusion under FR1 (fixed ratio of 1) and FR5 schedules of reinforcement [181]. Taken together, these studies are consistent with a potential role for a NT agonist to treat nicotine dependence.

3.4. Cocaine

NT is also a candidate for regulation of cocaine’s rewarding properties. However, NT knockout (KO) mice did not differ from wild type (WT) or heterozygous mice in most measures of locomotor activity and conditioned place preference paradigms [182], suggesting a limited role for NT in cocaine addiction. In contrast, NT mediates the dopamine D1 receptor potentiation at GABAA synapses in the oval bed nucleus of the stria terminalis. These changes were positively correlated with motivation in rats to self-administer cocaine [183]. Studies with NT antagonists have shown mixed results. When tested against cocaine-induced locomotor sensitization, the NT antagonist SR48692 given intraperitoneally decreases locomotor activity, but only if given over a two-week period [184]. In contrast, injections of SR 48692 into the NA shell enhance cocaine self-administration in a reinstatement paradigm [185]. NT (8–13) microinjected into the ventral pallidum (VP) reverses cocaine-induced decrease in GABA release, and attenuates cue-induced reinstatement, but paradoxically potentiates cocaine-primed reinstatement [186]. In summary, concerning NT-cocaine interactions, studies show inconsistent results; limited effects, synergy, or antagonism. Some of the contradictions stem from localized vs. whole brain interventions. In addition, SR 48692, a NTS-selective antagonist, has agonist properties at NTS2 [187]. Additional studies with whole brain exposure to NT agonists will be of interest to determine whether NT analogs may play a role in management of cocaine dependence.

3.5. Amphetamine

Amphetamine administration results in NT release in several brain regions including VTA, NA, and prefrontal cortex [188,189]. Studies with NT antagonists in addiction models with amphetamine have shown varying results. Injection of the NT antagonist SR 142948A into the VTA prior to amphetamine exposure prevent the development of sensitization. However, systemic administration of SR 142948A had no effect, underscoring the fact that local NT effects may not predict whole brain responses [190]. In another study, animals treated with SR 48692 displayed higher rates of locomotor response on day seven, but not day one, compared to those treated with amphetamine alone [191]. Additionally, when SR 48692 was given intraperitoneally, chronic NT blockade significantly reduced locomotor sensitization to amphetamine in rats, but at doses higher than usually required for blockade of acute NT effects [192]. In mice, the effect of a single dose of SR 48692 was able to block expression of amphetamine sensitization [193]. NT agonists have also been shown to block effects of amphetamine, although many of the studies have employed amphetamine challenge in animal models of schizophrenia, rather than animal models of addiction. However, in the majority of those studies, NT agonists have shown antipsychotic-like activity [22], which argues against NT as a primary mediator of amphetamine’s addicting effects. A NT analog, NT69L, blocks d-amphetamine-induced hyperactivity in rats [146]. Another brain-penetrating NT analog, PD149163, significantly reduced locomotor effects of amphetamine, and the effectiveness of the NT analog was not diminished after nine consecutive daily administrations [194].

3.6. Methamphetamine

Methamphetamine presumably exerts many of its highly addictive effects via basal ganglia dopamine systems [195], and also influences NT content in these structures. In one study NT content rose 210% in dorsal striatum and 202% in substantia nigra in a contingent response paradigm; significantly more than the non-contingent response to methamphetamine in yoked control animals [196]. In that same study, animals were pretreated with either the NT agonist PD149163 (given subcutaneously) or the NT antagonist SR 48692. Lever pressing decreased dramatically following agonist administration, but was unchanged by antagonist. Interestingly, in another study, low dose methamphetamine (0.5 mg/kg) almost doubled NT concentrations in medial striatum and NA; however, high dose methamphetamine (15 mg/kg) did not alter extracellular NT in these structures, compared to pretreatment levels [197]. One clinical implication of these findings according to the authors is that loss of inhibitory influence of endogenous NT after high dose methamphetamine exposure may lead to unchecked dopamine excess and contribute to psychotic symptoms seen in abusers. In a study of human postmortem brain tissue in chronic (greater than one year) methamphetamine abusers, NT levels were reduced compared to those for matched controls in caudate and putamen, and unchanged in NA [198]. Results are in contrast to that seen in most animal studies, but may reflect adaptation that occurred with long-term methamphetamine abuse.

3.7. Neurotensin and Alcohol

Several studies link NT to alcohol abuse. NTS1−/− mice demonstrate increased alcohol consumption compared to that for wild-type littermates when given free choice between alcohol and water, an effect blocked in wild type but not knockout animals by NT69L [169]. In this study, NTS1−/− mice were relatively insensitive to alcohol-induced ataxia, supporting the theory that NTS1 mediates alcohol intoxication and consumption. Comparable studies in NTS2 knockout mice showed decreased sensitivity to hypnotic effects, along with increased consumption of alcohol, but no differences were observed between knockout and wild type animals on ataxic effects. NT69L reduced alcohol intake in both NTS2−/− and wild-type mice [170]. Rats bred to be alcohol-preferring show a more arousing response to alcohol, behaviorally and on electroencephalogram (EEG), compared to non-preferring animals. These findings are similar to responses of human alcohol abusers who also experience less sedation and more arousal from alcohol than do social drinkers. Lower concentrations of NT were found in frontal cortex of alcohol-preferring rats, and differences in EEG frequencies between the groups were attenuated by administration of NT [199]. NT69L, which acts at both the high affinity NTS1 and lower affinity NTS2, predominately acts to reduce alcohol consumption through NTS1. NT69L modulates changes in dopamine and glutamate produced by alcohol in the striatum [200].
A growing body of evidence supports a role for NT in addiction, particularly for psychostimulants and alcohol. However, NT’s actions are complex and sometimes seemingly contradictory, depending on site of administration. Both NT agonists and antagonists have shown potential utility in addiction models. However, at least for psychostimulant addiction, effectiveness of NT antagonists has generally required chronic treatment, and chronic blockade of the receptors may lead to receptor up-regulation, increased NT synthesis and release [201]. Further studies with NT agonists given extracranially will help to clarify whether such compounds are useful therapies for substance use disorders. Table 4 summarizes animal behavioral studies implicating NT in the treatment of drug addiction.
Table 4. Animal behavioral studies implicating NT in the treatment of drug addiction.
Table 4. Animal behavioral studies implicating NT in the treatment of drug addiction.
Blockade of nicotine-induced hyperactivity[179]
Blockade of initiation and expression of sensitization to nicotine[180]
Blockade of nicotine self-administration[181]
Attenuate nicotine self-administration in alcohol-dependent rats[168]
Attenuate amphetamine-induced activity[146]
Attenuate cocaine-induced hyperactivity[146]
Decrease lever pressing for methamphetamine[196]
Decrease alcohol intake[169,170]

4. Neurotensin and Autism

4.1. Overview

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is diagnostically classified based on the persistence of both social behavioral deficits and the presence of restricted, repetitive behaviors [202]. These restricted and repetitive behaviors can vary greatly amongst individuals with ASD and can range from simple motor stereotypies and self-injurious behavior to insistence on sameness/routines and restricted, circumscribed interests [203]. These patterns of behavior are extremely inflexible in individuals with ASD and they impair daily functioning. Unfortunately, our understanding of the neuropathology that mediates these repetitive behaviors is limited and our strategies for pharmacological treatment are equally inadequate. Given that a vast majority of mental illnesses are best treated with a combination of two or more therapy types, reducing repetitive behavior with pharmacotherapy may improve responses to behavioral and occupational therapies for the other symptoms of ASD.
Phenotypic heterogeneity within the repetitive behavior domain and across the other aberrant behavioral characteristics associated with ASD (e.g., irritability, impulsivity, and aggression) has made the study of the neuroanatomical and neurochemical bases for these behavioral disorders very difficult. Moreover, this phenotypic diversity also significantly complicates clinical trials for novel pharmacological treatment [204]. As such, psychiatrists have been confined to only a few classes of drugs to try to reduce restricted, repetitive behaviors and none of these has proven safe and effective for a large majority of individuals with ASD. APDs are commonly prescribed to individuals with ASD and both risperidone and aripiprazole are FDA-approved for the treatment of irritability. These drugs are also commonly prescribed “off-label” (non-approved by FDA) for the reduction of impulsivity, aggression, and repetitive behaviors. As stated previously, side effects of APDs include weight gain, motor side effects, and sedation. The marginal efficacy for any pharmacological treatments of repetitive behaviors in individuals with ASD leaves much to be desired and suggests that we must improve our understanding of the neuropathology that mediates repetitive behaviors in order to elucidate more targeted compounds for repetitive behavior remediation.

4.2. Neurotensin, Repetitive Behavior, and Basal Ganglia Circuitry

As we have discussed, NT is described as an endogenous antipsychotic drug based on its close association with dopaminergic neurotransmission systems and its effects in animal models that predict antipsychotic effects in humans. Specifically, intracerebroventricular administration of both NT and APDs reduce psychostimulant-induced hyperactivity [205] and APDs increase NT concentrations in NA and dorsal striatum [118], effects that might confer the biological basis of the therapeutic response.
The NT system is also closely associated with glutamatergic and GABAergic neurotransmission. These three neurochemical systems—dopamine, glutamate, and GABA—all descend and interact in the basal ganglia nuclei. Cortico-basal ganglia circuitry mediates repetitive behavior, as demonstrated by neuroimaging studies in the diverse patient populations that exhibit repetitive behavior, including ASD [206,207,208,209,210,211,212,213]. Administration of NT causes increased release of glutamate and GABA from neurons in the cortex, striatum, and globus pallidus [97,214]. It also causes depolarization of indirect basal ganglia pathway neurons [215].

4.3. Animal Models of Repetitive Behavior

Repetitive behavior is exhibited in a wide variety of species and across a wide range of environments (though impoverishment and restriction are common traits across these environments). These abnormal behaviors can also be the consequence of genetic and pharmacological manipulations. Knockout mouse models that alter excitatory synapse development and structure commonly exhibit repetitive behaviors [216,217,218,219], as do rodents being administered dopamine and glutamate agonists. These findings further support the role of cortico-basal ganglia circuitry dys-regulation in repetitive behavior. In addition, environmental restriction models of repetitive behavior with the use of both inbred and outbred strains of mice have revealed significant indirect basal ganglia pathway dysfunction [220,221,222]. This dysfunction can be reversed by both pharmacological manipulations and environmental enrichment that change indirect basal ganglia pathway function [223,224,225]. Based on the interactions between NT signaling and indirect basal ganglia pathway function, we hypothesize that NT targeted drugs may offer significant pharmacological efficacy for reduction of repetitive behaviors in both animal models and individuals with ASD.

4.4. Neurotensin and ASD

NT has not received much attention as a possible factor in the pathophysiology or in the treatment of ASD [226]. One small study found significantly higher levels of serum NT in children with ASD relative to control children [227], though a correlation with repetitive behaviors or any other ASD-related behaviors was not achieved. In fact, elevated NT levels in the periphery may play a role in the dys-regulated peripheral systems that are associated with ASD, including immune reactivity, gastrointestinal problems, feeding difficulties, and sensory processing. NT stimulates the release of cellular mitochondrial DNA, which is elevated in serum of children with ASD [228]. Extracellular mitochondrial DNA, induced by NT release, causes elevation of the same cytokine precursors and cytokines (e.g., IL-6, NF-kB; [229]) that are overly expressed in the brain of individuals with ASD [230]. In addition, gastrointestinal symptoms correlate with ASD severity [231] and NT serves various functions in the gastrointestinal tract [232]. NT is also an anorexigenic neuropeptide [233] that may contribute to the feeding problems that are commonly exhibited by children with ASD [234]. Lastly, NT transmission mediates opioid-independent analgesia, as well as stimulates the stress-related hypothalamic-pituitary-adrenal (HPA) axis, two systems that are dys-regulated in some children with ASD [235].
Taken together several lines of evidence lead us to hypothesize that NT systems may be dys-regulated in ASD and may offer a target for clinically effective reduction in ASD symptoms. As is the case with drug addiction, the actions of NT are complex and the direction of change needed in NT function may be different in the CNS versus the periphery. Furthermore, the regulation of membrane receptors following NT-based treatments is multifaceted [2] and differs across acute and chronic administration protocols and NT receptor subtypes [236,237]. As such, it will be important to decipher the role of an agonist or antagonist treatment in cell body or terminal regions and which receptor subtypes will be most effective as targets to reduce repetitive behaviors. Targeting NT heteromeric receptor complexes (e.g., NTS1/NMDA and NTS1/D2) may also prove to be a valid pharmacological approach. Although many questions still remain, pursuing NT-targeted drugs may offer better therapeutic efficacy for treatment of repetitive behaviors over the commonly prescribed APDs and may also be of benefit treating other non-CNS problems commonly reported in individuals with ASD.

5. Conclusions

NT is a tridecapeptide that is found in the CNS. It behaves as a neurotransmitter in the brain and acts as a neuromodulator to several neurotransmitter systems including dopaminergic, sertonergic, GABAergic, glutamatergic, and cholinergic systems. Due to its association with such a wide variety of neurotransmitters, NT has been implicated in the pathophysiology of major mental disorders such as schizophrenia, drug abuse, and autism.
The use of NT analogs, that can be injected systemically, can cross the blood-brain barrier, show promising effects in animal models of psychosis without causing signs that are predictive of extrapyramidal side effects. Additionally, NT analogs are effective in blocking hyperactivity caused by acute administration of d-amphetamine, cocaine, nicotine, and alcohol in rats and mice, as well as sensitization to these psychostimulants. NT analogs also attenuate nicotine self-administration and reduce alcohol consumption. Furthermore, recent studies suggest that the NT system may be dys-regulated in ASD and preliminary data show encouraging effects of NT analogs in treating repetitive behaviors characteristic of ASD in mice. NT analogs hold great promise as a therapeutic agent for schizophrenia, psychostimulant abuse, and ASD.


This work was supported by Mayo Foundation for Medical Education and Research. Supported in part by the National Institutes of Health (NIH) and National Center for Research Resources (NCRR) CTSA grant UL1 TR000064 and KL2TR000065.

Author Contributions

Mona Boules planned the initial version of the review, provided oversight of all work, wrote the introduction and the NT and schizophrenia section, and prepared all tables. Paul Fredrickson wrote the section on NT and psychostimulant abuse. Amber Muehlmann wrote the NT and autism section. Elliott Richelson edited and reviewed the manuscript.

Conflicts of interest

The authors declare no conflict of interest.


  1. Carraway, R.; Bhatnagar, Y.M. Isolation, structure and biologic activity of chicken intestinal neurotensin. Peptides 1980, 1, 167–174. [Google Scholar] [CrossRef]
  2. Hermans, E.; Maloteaux, J.M. Mechanisms of regulation of neurotensin receptors. Pharmacol. Ther. 1998, 79, 89–104. [Google Scholar] [CrossRef]
  3. Mazella, J. Sortilin/neurotensin receptor-3: A new tool to investigate neurotensin signaling and cellular trafficking? Cell Signal. 2001, 13, 1–6. [Google Scholar] [CrossRef]
  4. Tanaka, K.; Masu, M.; Nakanishi, S. Structure and functional expression of the cloned rat neurotensin receptor. Neuron 1990, 4, 847–854. [Google Scholar] [CrossRef]
  5. Chalon, P.; Vita, N.; Kaghad, M.; Guillemot, M.; Bonnin, J.; Delpech, B.; Le Fur, G.; Ferrara, P.; Caput, D. Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett. 1996, 386, 91–94. [Google Scholar] [CrossRef]
  6. Mazella, J.; Botto, J.M.; Guillemare, E.; Coppola, T.; Sarret, P.; Vincent, J.P. Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain. J. Neurosci. 1996, 16, 5613–5620. [Google Scholar]
  7. Vita, N.; Laurent, P.; Lefort, S.; Chalon, P.; Dumont, X.; Kaghad, M.; Gully, D.; Le Fur, G.; Ferrara, P.; Caput, D. Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor. FEBS Lett. 1993, 317, 139–142. [Google Scholar] [CrossRef]
  8. Vincent, J.P.; Mazella, J.; Kitabgi, P. Neurotensin and neurotensin receptors. Trends Pharmacol. Sci. 1999, 20, 302–309. [Google Scholar] [CrossRef]
  9. Gilbert, J.A.; Richelson, E. Neurotensin stimulates formation of cyclic GMP in murine neuroblastoma clone N1E-115. Eur. J. Pharmacol. 1984, 99, 245–246. [Google Scholar] [CrossRef]
  10. Watson, M.A.; Yamada, M.; Cusack, B.; Veverka, K.; Bolden-Watson, C.; Richelson, E. The rat neurotensin receptor expressed in Chinese hamster ovary cells mediates the release of inositol phosphates. J. Neurochem. 1992, 59, 1967–1970. [Google Scholar] [CrossRef]
  11. Yamada, M.; Richelson, E. Role of signal transduction systems in neurotensin receptor down-regulation induced by agonist in murine neuroblastoma clone N1E-115 cells. J. Pharmacol. Exp. Ther. 1993, 267, 128–133. [Google Scholar]
  12. Hermans, E.; Gailly, P.; Octave, J.N.; Maloteaux, J.M. Rapid desensitization of agonist-induced calcium mobilization in transfected PC12 cells expressing the rat neurotensin receptor. Biochem. Biophys. Res. Commun. 1994, 198, 400–407. [Google Scholar] [CrossRef]
  13. Slusher, B.S.; Zacco, A.E.; Maslanski, J.A.; Norris, T.E.; McLane, M.W.; Moore, W.C.; Rogers, N.E.; Ignarro, L.J. The cloned neurotensin receptor mediates cyclic GMP formation when coexpressed with nitric oxide synthase cDNA. Mol. Pharmacol. 1994, 46, 115–121. [Google Scholar]
  14. Poinot-Chazel, C.; Portier, M.; Bouaboula, M.; Vita, N.; Pecceu, F.; Gully, D.; Monroe, J.G.; Maffrand, J.P.; Le Fur, G.; Casellas, P. Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24. Biochem. J. 1996, 320, 145–151. [Google Scholar]
  15. Lopez Ordieres, M.G.; Rodriguez de Lores Arnaiz, G. Neurotensin inhibits neuronal Na+, K+-ATPase activity through high affinity peptide receptor. Peptides 2000, 21, 571–576. [Google Scholar] [CrossRef]
  16. Trudeau, L.E. Neurotensin regulates intracellular calcium in ventral tegmental area astrocytes: Evidence for the involvement of multiple receptors. Neuroscience 2000, 97, 293–302. [Google Scholar] [CrossRef]
  17. St-Gelais, F.; Jomphe, C.; Trudeau, L.E. The role of neurotensin in central nervous system pathophysiology: What is the evidence? J. Psychiatry Neurosci. 2006, 31, 229–245. [Google Scholar]
  18. Mazella, J.; Vincent, J.P. Functional roles of the NTS2 and NTS3 receptors. Peptides 2006, 27, 2469–2475. [Google Scholar] [CrossRef]
  19. Sarret, P.; Krzywkowski, P.; Segal, L.; Nielsen, M.S.; Petersen, C.M.; Mazella, J.; Stroh, T.; Beaudet, A. Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system. J. Comp. Neurol. 2003, 461, 483–505. [Google Scholar] [CrossRef]
  20. Martin, S.; Vincent, J.P.; Mazella, J. Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J. Neurosci. 2003, 23, 1198–1205. [Google Scholar]
  21. Mustain, W.C.; Rychahou, P.G.; Evers, B.M. The role of neurotensin in physiologic and pathologic processes. Curr. Opin. Endocrinol. Diabetes Obes. 2011, 18, 75–82. [Google Scholar] [CrossRef]
  22. Boules, M.; Li, Z.; Smith, K.; Fredrickson, P.; Richelson, E. Diverse roles of neurotensin agonists in the central nervous system. Front. Endocrinol. 2013, 4, 1–16. [Google Scholar]
  23. Freedman, R. Schizophrenia. New Engl. J. Med. 2003, 349, 1738–1749. [Google Scholar] [CrossRef]
  24. Lewis, D.A.; Lieberman, J.A. Catching up on schizophrenia: Natural history and neurobiology. Neuron 2000, 28, 325–334. [Google Scholar] [CrossRef]
  25. Newman, S.C.; Bland, R.C. Mortality in a cohort of patients with schizophrenia: A record linkage study. Can. J. Psychiatry 1991, 36, 239–245. [Google Scholar]
  26. Carlsson, A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1988, 1, 179–186. [Google Scholar] [CrossRef]
  27. Howes, O.D.; Kapur, S. The dopamine hypothesis of schizophrenia: Version III—The final common pathway. Schizophr. Bull. 2009, 35, 549–562. [Google Scholar] [CrossRef]
  28. Snyder, S.H. The dopamine hypothesis of schizophrenia: Focus on the dopamine receptor. Am. J. Psychiatry 1976, 133, 197–202. [Google Scholar]
  29. Toda, M.; Abi-Dargham, A. Dopamine hypothesis of schizophrenia: Making sense of it all. Curr. Psychiatry Rep. 2007, 9, 329–336. [Google Scholar] [CrossRef]
  30. Carlsson, A.; Waters, N.; Waters, S.; Carlsson, M.L. Network interactions in schizophrenia—Therapeutic implications. Brain Res. Brain Res. Rev. 2000, 31, 342–349. [Google Scholar] [CrossRef]
  31. Weinberger, D.R. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 1987, 44, 660–669. [Google Scholar] [CrossRef]
  32. Alagarsamy, S.; Rouse, S.T.; Junge, C.; Hubert, G.W.; Gutman, D.; Smith, Y.; Conn, P.J. NMDA-induced phosphorylation and regulation of mGluR5. Pharmacol. Biochem. Behav. 2002, 73, 299–306. [Google Scholar] [CrossRef]
  33. Henry, S.A.; Lehmann-Masten, V.; Gasparini, F.; Geyer, M.A.; Markou, A. The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 2002, 43, 1199–1209. [Google Scholar] [CrossRef]
  34. Luccini, E.; Musante, V.; Neri, E.; Brambilla Bas, M.; Severi, P.; Raiteri, M.; Pittaluga, A. Functional interactions between presynaptic NMDA receptors and metabotropic glutamate receptors co-expressed on rat and human noradrenergic terminals. Br. J. Pharmacol. 2007, 151, 1087–1094. [Google Scholar]
  35. Tsai, G.; Coyle, J.T. Glutamatergic mechanisms in schizophrenia. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 165–179. [Google Scholar] [CrossRef]
  36. Carlsson, M.; Carlsson, A. Interactions between glutamatergic and monoaminergic systems within the basal ganglia—Implications for schizophrenia and Parkinson’s disease. Trends Neurosci. 1990, 13, 272–276. [Google Scholar] [CrossRef]
  37. Marek, G.J.; Behl, B.; Bespalov, A.Y.; Gross, G.; Lee, Y.; Schoemaker, H. Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: Too little juice or a miswired brain? Mol. Pharmacol. 2010, 77, 317–326. [Google Scholar] [CrossRef]
  38. Chartoff, E.H.; Heusner, C.L.; Palmiter, R.D. Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists. Neuropsychopharmacology 2005, 30, 1324–1333. [Google Scholar]
  39. Olney, J.W.; Newcomer, J.W.; Farber, N.B. NMDA receptor hypofunction model of schizophrenia. J. Psychiatr. Res. 1999, 33, 523–533. [Google Scholar] [CrossRef]
  40. Javitt, D.C.; Zukin, S.R. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 1991, 148, 1301–1308. [Google Scholar]
  41. Brody, S.A.; Conquet, F.; Geyer, M.A. Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology 2004, 172, 187–195. [Google Scholar] [CrossRef]
  42. Chiamulera, C.; Epping-Jordan, M.P.; Zocchi, A.; Marcon, C.; Cottiny, C.; Tacconi, S.; Corsi, M.; Orzi, F.; Conquet, F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat. Neurosci. 2001, 4, 873–874. [Google Scholar] [CrossRef]
  43. Lu, Y.M.; Jia, Z.; Janus, C.; Henderson, J.T.; Gerlai, R.; Wojtowicz, J.M.; Roder, J.C. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 1997, 17, 5196–5205. [Google Scholar]
  44. Matosin, N.; Newell, K.A. Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia. Neurosci. Biobehav. Rev. 2013, 37, 256–268. [Google Scholar] [CrossRef]
  45. Homayoun, H.; Stefani, M.R.; Adams, B.W.; Tamagan, G.D.; Moghaddam, B. Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release. Neuropsychopharmacol 2004, 29, 1259–1269. [Google Scholar] [CrossRef]
  46. Pietraszek, M.; Gravius, A.; Schafer, D.; Weil, T.; Trifanova, D.; Danysz, W. mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition. Neuropharmacology 2005, 49, 73–85. [Google Scholar] [CrossRef]
  47. Vales, K.; Svoboda, J.; Benkovicova, K.; Bubenikova-Valesova, V.; Stuchlik, A. The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801. Eur. J. Pharmacol. 2010, 639, 91–98. [Google Scholar] [CrossRef]
  48. Zou, D.; Huang, J.; Wu, X.; Li, L. Metabotropic glutamate subtype 5 receptors modulate fear-conditioning induced enhancement of prepulse inhibition in rats. Neuropharmacology 2007, 52, 476–486. [Google Scholar] [CrossRef]
  49. Robbins, T.W.; Murphy, E.R. Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition. Trends Pharmacol. Sci. 2006, 27, 141–148. [Google Scholar] [CrossRef]
  50. Joyce, J.N. The dopamine hypothesis of schizophrenia: Limbic interactions with serotonin and norepinephrine. Psychopharmacology (Berl) 1993, 112, S16–S34. [Google Scholar] [CrossRef]
  51. Tort, A.B.; Souza, D.O.; Lara, D.R. Theoretical insights into the mechanism of action of atypical antipsychotics. Prog. Neuropsychopharmacol. Biol. Psychiatry 2006, 30, 541–548. [Google Scholar] [CrossRef]
  52. Remington, G. Refractory schizophrenia: Adding aripiprazole to clozapine reduces negative but not overall symptoms. Evid.-based Ment. Health 2009, 12, 51. [Google Scholar] [CrossRef]
  53. Gardell, L.R.; Vanover, K.E.; Pounds, L.; Johnson, R.W.; Barido, R.; Anderson, G.T.; Veinbergs, I.; Dyssegaard, A.; Brunmark, P.; Tabatabaei, A.; et al. ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models. J. Pharmacol. Exp. Ther. 2007, 322, 862–870. [Google Scholar] [CrossRef]
  54. Abbas, A.; Roth, B.L. Pimavanserin tartrate: A 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opinion Pharmacother. 2008, 9, 3251–3259. [Google Scholar] [CrossRef]
  55. Creese, I.; Burt, D.R.; Snyder, S.H. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976, 192, 481–483. [Google Scholar] [CrossRef]
  56. Andersson, C.; Chakos, M.; Mailman, R.; Lieberman, J. Emerging roles for novel antipsychotic medications in the treatment of schizophrenia. Psychiatri. Clin. North Am. 1998, 21, 151–179. [Google Scholar] [CrossRef]
  57. Salimi, K.; Jarskog, L.F.; Lieberman, J.A. Antipsychotic drugs for first-episode schizophrenia: A comparative review. CNS Drugs 2009, 23, 837–855. [Google Scholar] [CrossRef]
  58. Cordoba, O.A. Antipsychotic medications: Clinical use and effectiveness. Hosp Pract (Off Ed) 1981, 16, 99–101. [Google Scholar]
  59. Meltzer, H.Y.; Matsubara, S.; Lee, J.C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 1989, 251, 238–246. [Google Scholar]
  60. Meltzer, H.Y. Update on typical and atypical antipsychotic drugs. Annu. Rev. Med. 2013, 64, 393–406. [Google Scholar] [CrossRef]
  61. Kane, J.M. Addressing side effects from antipsychotic treatment in schizophrenia. J. Clinic. Psychiatr. 2011, 72, e07. [Google Scholar] [CrossRef]
  62. Krystal, J.H.; Mathew, S.J.; D’Souza, D.C.; Garakani, A.; Gunduz-Bruce, H.; Charney, D.S. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 2010, 24, 669–693. [Google Scholar]
  63. Patil, S.T.; Zhang, L.; Martenyi, F.; Lowe, S.L.; Jackson, K.A.; Andreev, B.V.; Avedisova, A.S.; Bardenstein, L.M.; Gurovich, I.Y.; Morozova, M.A.; et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized Phase 2 clinical trial. Nat. Med. 2007, 13, 1102–1107. [Google Scholar] [CrossRef]
  64. Gray, L.; van den Buuse, M.; Scarr, E.; Dean, B.; Hannan, A.J. Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: Association with N-methyl-D-aspartic acid receptor up-regulation. Int. J. Neuropsychopharmacol. 2009, 12, 45–60. [Google Scholar] [CrossRef]
  65. Matosin, N.; Frank, E.; Deng, C.; Huang, X.F.; Newell, K.A. Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment. Schizophr. Res. 2013, 146, 170–176. [Google Scholar] [CrossRef]
  66. Iasevoli, F.; Tomasetti, C.; Marmo, F.; Bravi, D.; Arnt, J.; de Bartolomeis, A. Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole. Psychopharmacology 2010, 212, 329–344. [Google Scholar]
  67. Greenbaum, D.; Colangelo, C.; Williams, K.; Gerstein, M. Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol. 2003, 4, 117. [Google Scholar] [CrossRef]
  68. Polese, D.; de Serpis, A.A.; Ambesi-Impiombato, A.; Muscettola, G.; de Bartolomeis, A. Homer 1a gene expression modulation by antipsychotic drugs: involvement of the glutamate metabotropic system and effects of D-cycloserine. Neuropsychopharmacol. 2002, 27, 906–913. [Google Scholar] [CrossRef]
  69. Shao, F.; Han, X.; Li, N.; Wang, W. Adolescent chronic apomorphine treatment impairs latent inhibition and reduces prefrontal cortex mGluR5 receptor expression in adult rats. Eur. J. Pharmacol. 2010, 649, 202–205. [Google Scholar] [CrossRef]
  70. D’Souza, D.C.; Singh, N.; Elander, J.; Carbuto, M.; Pittman, B.; Udo de Haes, J.; Sjogren, M.; Peeters, P.; Ranganathan, M.; Schipper, J. Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence. Neuropsychopharmacol. 2012, 37, 1036–1046. [Google Scholar] [CrossRef]
  71. Alberati, D.; Moreau, J.L.; Lengyel, J.; Hauser, N.; Mory, R.; Borroni, E.; Pinard, E.; Knoflach, F.; Schlotterbeck, G.; Hainzl, D.; et al. Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology 2012, 62, 1152–1161. [Google Scholar]
  72. Lane, H.Y.; Chang, Y.C.; Liu, Y.C.; Chiu, C.C.; Tsai, G.E. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: A randomized, double-blind, placebo-controlled study. Arch. Gen. Psychiatr. 2005, 62, 1196–1204. [Google Scholar] [CrossRef]
  73. Lane, H.Y.; Lin, C.H.; Huang, Y.J.; Liao, C.H.; Chang, Y.C.; Tsai, G.E. A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int. J. Neuropsychopharmacol. 2010, 13, 451–460. [Google Scholar] [CrossRef]
  74. Tsai, G.; Lane, H.Y.; Yang, P.; Chong, M.Y.; Lange, N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol. Psychiatr. 2004, 55, 452–456. [Google Scholar] [CrossRef]
  75. Citrome, L.; Volavka, J. Pharmacological management of acute and persistent aggression in forensic psychiatry settings. CNS Drugs 2011, 25, 1009–1021. [Google Scholar] [CrossRef]
  76. Chue, P. Glycine reuptake inhibition as a new therapeutic approach in schizophrenia: Focus on the glycine transporter 1 (GlyT1). Curr. Pharm. Des. 2013, 19, 1311–1320. [Google Scholar]
  77. Noetzel, M.J.; Jones, C.K.; Conn, P.J. Emerging approaches for treatment of schizophrenia: Modulation of glutamatergic signaling. Discov. Med. 2012, 14, 335–343. [Google Scholar]
  78. Krebs, M.; Leopold, K.; Hinzpeter, A.; Schaefer, M. Current schizophrenia drugs: Efficacy and side effects. Expert Opinion Pharmacother. 2006, 7, 1005–1016. [Google Scholar] [CrossRef]
  79. Brouard, A.; Pelaprat, D.; Dana, C.; Vial, M.; Lhiaubet, A.M.; Rostene, W. Mesencephalic dopaminergic neurons in primary cultures express functional neurotensin receptors. J. Neurosci. 1992, 12, 1409–1415. [Google Scholar]
  80. Palacios, J.M.; Kuhar, M.J. Neurotensin receptors are located on dopamine-containing neurones in rat midbrain. Nature 1981, 294, 587–589. [Google Scholar] [CrossRef]
  81. Alexander, M.J.; Leeman, S.E. Widespread expression in adult rat forebrain of mRNA encoding high-affinity neurotensin receptor. J. Comp. Neurol. 1998, 402, 475–500. [Google Scholar] [CrossRef]
  82. Kinkead, B.; Nemeroff, C.B. Neurotensin, schizophrenia, and antipsychotic drug action. Int. Rev. Neurobiol. 2004, 59, 327–349. [Google Scholar] [CrossRef]
  83. Shi, W.X.; Bunney, B.S. Neurotensin modulates autoreceptor mediated dopamine effects on midbrain dopamine cell activity. Brain Res. 1991, 543, 315–321. [Google Scholar] [CrossRef]
  84. Quirion, R.; Rowe, W.B.; Lapchak, P.A.; Araujo, D.M.; Beaudet, A. Distribution of neurotensin receptors in mammalian brain. What it is telling us about its interactions with other neurotransmitter systems. Annu. N. Y. Acad. Sci. 1992, 668, 109–119. [Google Scholar] [CrossRef]
  85. Binder, E.B.; Kinkead, B.; Owens, M.J.; Nemeroff, C.B. Neurotensin and dopamine interactions. Pharmacol. Rev. 2001, 53, 453–486. [Google Scholar]
  86. Fawaz, C.S.; Martel, P.; Leo, D.; Trudeau, L.E. Presynaptic action of neurotensin on dopamine release through inhibition of D(2) receptor function. BMC Neurosci. 2009, 10, 96. [Google Scholar] [CrossRef]
  87. Caceda, R.; Kinkead, B.; Nemeroff, C.B. Neurotensin: Role in psychiatric and neurological diseases. Peptides 2006, 27, 2385–2404. [Google Scholar]
  88. Diaz-Cabiale, Z.; Fuxe, K.; Narvaez, J.A.; Finetti, S.; Antonelli, T.; Tanganelli, S.; Ferraro, L. Neurotensin-induced modulation of dopamine D2 receptors and their function in rat striatum: Counteraction by a NTR1-like receptor antagonist. Neuroreport 2002, 13, 763–766. [Google Scholar] [CrossRef]
  89. Fuxe, K.; Von Euler, G.; Agnati, L.F.; Merlo Pich, E.; O’Connor, W.T.; Tanganelli, S.; Li, X.M.; Tinner, B.; Cintra, A.; Carani, C.; et al. Intramembrane interactions between neurotensin receptors and dopamine D2 receptors as a major mechanism for the neuroleptic-like action of neurotensin. Annu. N.Y. Acad. Sci. 1992, 668, 186–204. [Google Scholar] [CrossRef]
  90. Li, X.M.; Ferraro, L.; Tanganelli, S.; O’Connor, W.T.; Hasselrot, U.; Ungerstedt, U.; Fuxe, K. Neurotensin peptides antagonistically regulate postsynaptic dopamine D2 receptors in rat nucleus accumbens: A receptor binding and microdialysis study. J. Neural. Transm. Gen. Sect. 1995, 102, 125–137. [Google Scholar] [CrossRef]
  91. Burgevin, M.C.; Castel, M.N.; Quarteronet, D.; Chevet, T.; Laduron, P.M. Neurotensin increases tyrosine hydroxylase messenger RNA-positive neurons in substantia nigra after retrograde axonal transport. Neuroscience 1992, 49, 627–633. [Google Scholar] [CrossRef]
  92. Burgevin, M.C.; Laduron, P.M.; Quarteronnet, D.; Chevet, T.; Castel, M.N. Striatal injection of neurotensin increases tyrosine hydroxylase mRNA in substantia nigra. Annu. N. Y. Acad. Sci. 1992, 668, 311–313. [Google Scholar] [CrossRef]
  93. Borroto-Escuela, D.O.; Ravani, A.; Tarakanov, A.O.; Brito, I.; Narvaez, M.; Romero-Fernandez, W.; Corrales, F.; Agnati, L.F.; Tanganelli, S.; Ferraro, L.; et al. Dopamine D2 receptor signaling dynamics of dopamine D2-neurotensin 1 receptor heteromers. Biochemi. Biophys. Res. Comm. 2013, 435, 140–146. [Google Scholar]
  94. Carlsson, A.; Waters, N.; Carlsson, M.L. Neurotransmitter interactions in schizophrenia—Therapeutic implications. Biol. Psychiatry 1999, 46, 1388–1395. [Google Scholar] [CrossRef]
  95. O’Connor, W.T. Functional neuroanatomy of the ventral striopallidal GABA pathway. New sites of intervention in the treatment of schizophrenia. J. Neurosci. Meth. 2001, 109, 31–39. [Google Scholar] [CrossRef]
  96. Ferraro, L.; Tomasini, M.C.; Fuxe, K.; Agnati, L.F.; Mazza, R.; Tanganelli, S.; Antonelli, T. Mesolimbic dopamine and cortico-accumbens glutamate afferents as major targets for the regulation of the ventral striato-pallidal GABA pathways by neurotensin peptides. Brain Res. Rev. 2007, 55, 144–154. [Google Scholar] [CrossRef]
  97. Ferraro, L.; Beggiato, S.; Tomasini, M.C.; Fuxe, K.; Tanganelli, S.; Antonelli, T. Neurotensin regulates cortical glutamate transmission by modulating N-methyl-D-aspartate receptor functional activity: An in vivo microdialysis study. J. Neurosci. Res. 2011, 89, 1618–1626. [Google Scholar] [CrossRef]
  98. Chen, L.; Yung, K.K.; Yung, W.H. Neurotensin selectively facilitates glutamatergic transmission in globus pallidus. Neuroscience 2006, 141, 1871–1878. [Google Scholar] [CrossRef]
  99. Matsuyama, S.; Fukui, R.; Higashi, H.; Nishi, A. Regulation of DARPP-32 Thr75 phosphorylation by neurotensin in neostriatal neurons: involvement of glutamate signalling. Eur. J. Neurosci. 2003, 18, 1247–1253. [Google Scholar] [CrossRef]
  100. Ferraro, L.; Tomasini, M.C.; Fernandez, M.; Bebe, B.W.; O’Connor, W.T.; Fuxe, K.; Glennon, J.C.; Tanganelli, S.; Antonelli, T. Nigral neurotensin receptor regulation of nigral glutamate and nigroventral thalamic GABA transmission: A dual-probe microdialysis study in intact conscious rat brain. Neuroscience 2001, 102, 113–120. [Google Scholar] [CrossRef]
  101. Ferraro, L.; Tomasini, M.C.; Siniscalchi, A.; Fuxe, K.; Tanganelli, S.; Antonelli, T. Neurotensin increases endogenous glutamate release in rat cortical slices. Life Sci. 2000, 66, 927–936. [Google Scholar] [CrossRef]
  102. Sanz, B.; Exposito, I.; Mora, F. Effects of neurotensin on the release of glutamic acid in the prefrontal cortex and striatum of the rat. Neuroreport 1993, 4, 1194–1196. [Google Scholar]
  103. Tanganelli, S.; O’Connor, W.T.; Ferraro, L.; Bianchi, C.; Beani, L.; Ungerstedt, U.; Fuxe, K. Facilitation of GABA release by neurotensin is associated with a reduction of dopamine release in rat nucleus accumbens. Neuroscience 1994, 60, 649–657. [Google Scholar] [CrossRef]
  104. Kinkead, B.; Shahid, S.; Owens, M.J.; Nemeroff, C.B. Effects of acute and subchronic administration of typical and atypical antipsychotic drugs on the neurotensin system of the rat brain. J. Pharmacol. Exp. Ther. 2000, 295, 67–73. [Google Scholar]
  105. Levant, B.; Nemeroff, C.B. Further studies on the modulation of regional brain neurotensin concentrations by antipsychotic drugs: focus on haloperidol and BMY 14802. J. Pharmacol. Exp. Ther. 1992, 262, 348–355. [Google Scholar]
  106. Merchant, K.M.; Dobner, P.R.; Dorsa, D.M. Differential effects of haloperidol and clozapine on neurotensin gene transcription in rat neostriatum. J. Neurosci. 1992, 12, 652–663. [Google Scholar]
  107. Merchant, K.M.; Miller, M.A.; Ashleigh, E.A.; Dorsa, D.M. Haloperidol rapidly increases the number of neurotensin mRNA-expressing neurons in neostriatum of the rat brain. Brain Res. 1991, 540, 311–314. [Google Scholar] [CrossRef]
  108. Myers, B.; Levant, B.; Bissette, G.; Nemeroff, C.B. Pharmacological specificity of the increase in neurotensin concentrations after antipsychotic drug treatment. Brain Res. 1992, 575, 325–328. [Google Scholar] [CrossRef]
  109. Merchant, K.M.; Dorsa, D.M. Differential induction of neurotensin and c-fos gene expression by typical versus atypical antipsychotics. Proc. Natl. Acad. Sci. USA. 1993, 90, 3447–3451. [Google Scholar] [CrossRef]
  110. Bolden-Watson, C.; Watson, M.A.; Murray, K.D.; Isackson, P.J.; Richelson, E. Haloperidol but not clozapine increases neurotensin receptor mRNA levels in rat substantia nigra. J. Neurochem. 1993, 61, 1141–1143. [Google Scholar] [CrossRef]
  111. Giardino, L.; Calza, L.; Piazza, P.V.; Zanni, M.; Amato, G. DA2/NT receptor balance in the mesostriatal and mesolimbocortical systems after chronic treatment with typical and atypical neuroleptic drugs. Brain Res. 1990, 532, 140–145. [Google Scholar] [CrossRef]
  112. Radke, J.M.; MacLennan, A.J.; Beinfeld, M.C.; Bissette, G.; Nemeroff, C.B.; Vincent, S.R.; Fibiger, H.C. Effects of short- and long-term haloperidol administration and withdrawal on regional brain cholecystokinin and neurotensin concentrations in the rat. Brain Res. 1989, 480, 178–183. [Google Scholar] [CrossRef]
  113. Levant, B.; Bissette, G.; Nemeroff, C.B. Effects of anticholinergic drugs on regional brain neurotensin concentrations. Eur. J. Pharmacol. 1989, 165, 327–330. [Google Scholar] [CrossRef]
  114. Levant, B.; Bissette, G.; Widerlov, E.; Nemeroff, C.B. Alterations in regional brain neurotensin concentrations produced by atypical antipsychotic drugs. Regul. Pept. 1991, 32, 193–201. [Google Scholar]
  115. Bissette, G.; Nemeroff, C.B. Neurotensin and the mesocorticolimbic dopamine system. Annu. NY Acad. Sci. 1988, 537, 397–404. [Google Scholar] [CrossRef]
  116. See, R.E.; Lynch, A.M.; Aravagiri, M.; Nemeroff, C.B.; Owens, M.J. Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats. Brain Res. 1995, 704, 202–209. [Google Scholar] [CrossRef]
  117. Huang, W.; Hanson, G.R. Differential effect of haloperidol on release of neurotensin in extrapyramidal and limbic systems. Eur. J. Pharmacol. 1997, 332, 15–21. [Google Scholar] [CrossRef]
  118. Govoni, S.; Hong, J.S.; Yang, H.Y.; Costa, E. Increase of neurotensin content elicited by neuroleptics in nucleus accumbens. J. Pharmacol. Exp. Ther. 1980, 215, 413–417. [Google Scholar]
  119. Merchant, K.M.; Letter, A.A.; Gibb, J.W.; Hanson, G.R. Changes in the limbic neurotensin systems induced by dopaminergic drugs. Eur. J. Pharmacol. 1988, 153, 1–9. [Google Scholar] [CrossRef]
  120. Gruber, S.H.; Nomikos, G.G.; Mathe, A.A. Effects of haloperidol and risperidone on neurotensin levels in brain regions and neurotensin efflux in the ventral striatum of the rat. Neuropsychopharmacology 2002, 26, 595–604. [Google Scholar] [CrossRef]
  121. Bissette, G.; Nemeroff, C.B.; Loosen, P.T.; Prange, A.J.; Lipton, M.A. Hypothermia and intolerance to cold induced by intracisternal administration of the hypothalamic peptide neurotensin. Nature 1976, 262, 607–609. [Google Scholar] [CrossRef]
  122. Sarhan, S.; Hitchcock, J.M.; Grauffel, C.A.; Wettstein, J.G. Comparative antipsychotic profiles of neurotensin and a related systemically active peptide agonist. Peptides 1997, 18, 1223–1227. [Google Scholar] [CrossRef]
  123. Nemeroff, C.B.; Bissette, G.; Prange, A.J.; Loosen, P.T.; Barlow, T.S.; Lipton, M.A. Neurotensin: Central nervous system effects of a hypothalamic peptide. Brain Res. 1977, 128, 485–496. [Google Scholar] [CrossRef]
  124. Nemeroff, C.B.; Levant, B.; Myers, B.; Bissette, G. Neurotensin, antipsychotic drugs, and schizophrenia. Basic and clinical studies. Annu. NY Acad. Sci. 1992, 668, 146–156. [Google Scholar] [CrossRef]
  125. Jolicoeur, F.B.; de Michele, G.; Barbeau, A.; St-Pierre, S. Neurotensin affects hyperactivity but not stereotypy induced by pre and post synaptic dopaminergic stimulation. Neurosci. Biobehav. Rev. 1983, 7, 385–390. [Google Scholar] [CrossRef]
  126. Jolicoeur, F.B.; Gagne, M.A.; Rivest, R.; Drumheller, A.; St-Pierre, S. Atypical neuroleptic-like behavioral effects of neurotensin. Brain Res. Bull. 1993, 32, 487–491. [Google Scholar] [CrossRef]
  127. Stoessl, A.J. Effects of neurotensin in a rodent model of tardive dyskinesia. Neuropharmacology 1995, 34, 457–462. [Google Scholar] [CrossRef]
  128. Luttinger, D.; Nemeroff, C.B.; Prange, A.J. The effects of neuropeptides on discrete-trial conditioned avoidance responding. Brain Res. 1982, 237, 183–192. [Google Scholar] [CrossRef]
  129. Feifel, D.; Minor, K.L.; Dulawa, S.; Swerdlow, N.R. The effects of intra-accumbens neurotensin on sensorimotor gating. Brain Res. 1997, 760, 80–84. [Google Scholar] [CrossRef]
  130. Swerdlow, N.R.; Braff, D.L.; Taaid, N.; Geyer, M.A. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch. Gen. Psychiatry 1994, 51, 139–154. [Google Scholar]
  131. Nemeroff, C.B. Neurotensin: Perchance an endogenous neuroleptic? Biol. Psychiatry 1980, 15, 283–302. [Google Scholar]
  132. Kinkead, B.; Binder, E.B.; Nemeroff, C.B. Does neurotensin mediate the effects of antipsychotic drugs? Biol. Psychiatry 1999, 46, 340–351. [Google Scholar] [CrossRef]
  133. Cusack, B.; Boules, M.; Tyler, B.M.; Fauq, A.; McCormick, D.J.; Richelson, E. Effects of a novel neurotensin peptide analog given extracranially on CNS behaviors mediated by apomorphine and haloperidol. Brain Res. 2000, 856, 48–54. [Google Scholar] [CrossRef]
  134. Feifel, D.; Melendez, G.; Shilling, P.D. A systemically administered neurotensin agonist blocks disruption of prepulse inhibition produced by a serotonin-2A agonist. Neuropsychopharmacology 2003, 28, 651–653. [Google Scholar] [CrossRef]
  135. Shilling, P.D.; Richelson, E.; Feifel, D. The effects of systemic NT69L, a neurotensin agonist, on baseline and drug-disrupted prepulse inhibition. Behav. Brain Res. 2003, 143, 7–14. [Google Scholar] [CrossRef]
  136. Briody, S.; Boules, M.; Oliveros, A.; Fauq, I.; Richelson, E. Chronic NT69L potently prevents drug-induced disruption of prepulse inhibition without causing tolerance. Behav. Brain Res. 2010, 207, 118–124. [Google Scholar]
  137. Kinkead, B.; Dobner, P.R.; Egnatashvili, V.; Murray, T.; Deitemeyer, N.; Nemeroff, C.B. Neurotensin-deficient mice have deficits in prepulse inhibition: Restoration by clozapine but not haloperidol, olanzapine, or quetiapine. J. Pharmacol. Exp. Ther. 2005, 315, 256–264. [Google Scholar] [CrossRef]
  138. Feifel, D.; Pang, Z.; Shilling, P.D.; Melendez, G.; Schreiber, R.; Button, D. Sensorimotor gating in neurotensin-1 receptor null mice. Neuropharmacology 2010, 58, 173–178. [Google Scholar] [CrossRef]
  139. Feifel, D.; Reza, T.L.; Robeck, S.L. Pro-dopamine effects of neurotensin on sensorimotor gating deficits. Peptides 1997, 18, 1457–1460. [Google Scholar] [CrossRef]
  140. Feifel, D.; Melendez, G; Shilling, P.D. Reversal of sensorimotor gating deficits in Brattleboro rats by acute administration of clozapine and a neurotensin agonist, but not haloperidol: A potential predictive model for novel antipsychotic effects. Neuropsychopharmacology 2004, 29, 731–738. [Google Scholar] [CrossRef]
  141. Shilling, P.D.; Melendez, G.; Priebe, K; Richelson, E.; Feifel, D. Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT(2A) and an alpha(1) agonist. Psychopharmacology (Berl) 2004, 175, 353–359. [Google Scholar] [CrossRef]
  142. Secchi, R.L.; Sung, E.; Hedley, L.R.; Button, D.; Schreiber, R. The neurotensin agonist NT69L improves sensorimotor gating deficits in rats induced by a glutamatergic antagonist but not by dopaminergic agonists. Behav. Brain Res. 2009, 202, 192–197. [Google Scholar] [CrossRef]
  143. Geyer, M.A.; Ellenbroek, B. Animal behavior models of the mechanisms underlying antipsychotic atypicality. Prog. Neuropsychopharmacol. Biol. Psychiatry 2003, 27, 1071–1079. [Google Scholar] [CrossRef]
  144. Binder, E.B.; Kinkead, B.; Owens, M.J.; Kilts, C.D.; Nemeroff, C.B. Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: Evidence from animal models of sensorimotor gating. J. Neurosci. 2001, 21, 601–608. [Google Scholar]
  145. Binder, E.B.; Gross, R.E.; Nemeroff, C.B.; Kilts, C.D. Effects of neurotensin receptor antagonism on latent inhibition in Sprague-Dawley rats. Psychopharmacology (Berl) 2002, 161, 288–295. [Google Scholar]
  146. Boules, M.; Warrington, L.; Fauq, A.; McCormick, D.; Richelson, E. A novel neurotensin analog blocks cocaine- and D-amphetamine-induced hyperactivity. Eur. J. Pharmacol. 2001, 426, 73–76. [Google Scholar] [CrossRef]
  147. Boules, M.; McMahon, B.; Warrington, L.; Stewart, J.; Jackson, J.; Fauq, A.; McCormick, D.; Richelson, E. Neurotensin analog selective for hypothermia over antinociception and exhibiting atypical neuroleptic-like properties. Brain Res. 2001, 919, 1–11. [Google Scholar] [CrossRef]
  148. Boules, M.; Liang, Y.; Briody, S.; Miura, T.; Fauq, I.; Oliveros, A.; Wilson, M.; Khaniyev, S.; Williams, K.; Li, Z.; et al. NT79: A novel neurotensin analog with selective behavioral effects. Brain Res. 2010, 1308, 35–46. [Google Scholar]
  149. Li, Z.; Boules, M.; Williams, K.; Peris, J.; Richelson, E. The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex. Brain Res. 2010, 1311, 28–36. [Google Scholar]
  150. Snyder, S.H. Phencyclidine. Nature 1980, 285, 355–356. [Google Scholar] [CrossRef]
  151. Feifel, D.; Reza, T.L.; Wustrow, D.J.; Davis, M.D. Novel antipsychotic-like effects on prepulse inhibition of startle produced by a neurotensin agonist. J. Pharmacol. Exp. Ther. 1999, 288, 710–713. [Google Scholar]
  152. Holly, E.N.; Ebrecht, B.; Prus, A.J. The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats. Eur. Neuropsychopharmacol 2011, 21, 526–531. [Google Scholar] [CrossRef]
  153. Liang, Y.; Boules, M.; Li, Z.; Williams, K.; Miura, T.; Oliveros, A.; Richelson, E. Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice. Neuropharmacology 2010, 58, 1199–1205. [Google Scholar] [CrossRef]
  154. Li, Z.; Liang, Y.; Boules, M.; Gordillo, A.; Richelson, E. Effect of amphetamine on extracellular concentrations of amino acids in striatum in neurotensin subtype 1 and 2 receptor null mice: A possible interaction between neurotensin receptors and amino acid systems for study of schizophrenia. Neuropharmacology 2010, 58, 1174–1178. [Google Scholar]
  155. Li, Z.; Boules, M.; Williams, K.; Gordillo, A.; Li, S.; Richelson, E. Similarities in the behavior and molecular deficits in the frontal cortex between the neurotensin receptor subtype 1 knockout mice and chronic phencyclidine-treated mice: Relevance to schizophrenia. Neurobiol. Dis. 2010, 40, 467–477. [Google Scholar] [CrossRef]
  156. Garver, D.L.; Bissette, G.; Yao, J.K.; Nemeroff, C.B. Relation of CSF neurotensin concentrations to symptoms and drug response of psychotic patients. Am. J. Psychiatry. 1991, 148, 484–488. [Google Scholar]
  157. Lindstrom, L.H.; Widerlov, E.; Bisette, G.; Nemeroff, C. Reduced CSF neurotensin concentration in drug-free schizophrenic patients. Schizophr. Res. 1988, 1, 55–59. [Google Scholar] [CrossRef]
  158. Nemeroff, C.B.; Bissette, G.; Widerlov, E.; Beckmann, H.; Gerner, R.; Manberg, P.J.; Lindstrom, L.; Prange, A.J.; Gattaz, W.F. Neurotensin-like immunoreactivity in cerebrospinal fluid of patients with schizophrenia, depression, anorexia nervosa-bulimia, and premenstrual syndrome. J. Neuropsychiatry Clin. Neurosci. 1989, 1, 16–20. [Google Scholar]
  159. Sharma, R.P.; Janicak, P.G.; Bissette, G.; Nemeroff, C.B. CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder. Am. J. Psychiatry. 1997, 154, 1019–1021. [Google Scholar]
  160. Widerlov, E.; Lindstrom, L.H.; Besev, G.; Manberg, P.J.; Nemeroff, C.B.; Breese, G.R.; Kizer, J.S.; Prange, A.J. Subnormal CSF levels of neurotensin in a subgroup of schizophrenic patients: Normalization after neuroleptic treatment. Am. J. Psychiatry. 1982, 139, 1122–1126. [Google Scholar]
  161. Breslin, N.A.; Suddath, R.L.; Bissette, G.; Nemeroff, C.B.; Lowrimore, P.; Weinberger, D.R. CSF concentrations of neurotensin in schizophrenia: An investigation of clinical and biochemical correlates. Schizophr. Res. 1994, 12, 35–41. [Google Scholar] [CrossRef]
  162. Binder, E.B.; Kinkead, B.; Owens, M.J.; Nemeroff, C.B. The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs. Biol. Psychiatry 2001, 50, 856–872. [Google Scholar] [CrossRef]
  163. Dalack, G.W.; Healy, D.J.; Meador-Woodruff, J.H. Nicotine dependence in schizophrenia: Clinical phenomena and laboratory findings. Am. J. Psychiatry 1998, 155, 1490–1501. [Google Scholar]
  164. Boules, M.; Cusack, B.; Zhao, L.; Fauq, A.; McCormick, D.J.; Richelson, E. A novel neurotensin peptide analog given extracranially decreases food intake and weight in rodents. Brain Res. 2000, 865, 35–44. [Google Scholar] [CrossRef]
  165. Kim, E.R.; Leckstrom, A.; Mizuno, T.M. Impaired anorectic effect of leptin in neurotensin receptor 1-deficient mice. Behav. Brain Res. 2008, 194, 66–71. [Google Scholar] [CrossRef]
  166. Feifel, D.; Goldenberg, J.; Melendez, G.; Shilling, P.D. The acute and subchronic effects of a brain-penetrating, neurotensin-1 receptor agonist on feeding, body weight and temperature. Neuropharmacology 2010, 58, 195–198. [Google Scholar] [CrossRef]
  167. Koob, G.F.; Sanna, P.P.; Bloom, F.E. Neuroscience of addiction. Neuron 1998, 21, 467–476. [Google Scholar] [CrossRef]
  168. Boules, M.; Stennett, B.; Muhktar, N.; Li, Z.; Cai, S.; Richelson, E. Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats. J. Addiction Res. Ther. 2013, 4, 161. [Google Scholar] [CrossRef]
  169. Lee, M.R.; Hinton, D.J.; Song, J.Y.; Lee, K.W.; Choo, C.; Johng, H.; Unal, S.S.; Richelson, E.; Choi, D.S. Neurotensin receptor type 1 regulates ethanol intoxication and consumption in mice. Pharmacol. Biochem. Behav. 2010, 95, 235–241. [Google Scholar] [CrossRef]
  170. Lee, M.R.; Hinton, D.J.; Unal, S.S.; Richelson, E.; Choi, D.S. Increased ethanol consumption and preference in mice lacking neurotensin receptor type 2. Alcohol. Clin. Exp. Res. 2011, 35, 99–107. [Google Scholar] [CrossRef]
  171. Miller, D.K.; Wilkins, L.H.; Bardo, M.T.; Crooks, P.A.; Dwoskin, L.P. Once weekly administration of nicotine produces long-lasting locomotor sensitization in rats via a nicotinic receptor-mediated mechanism. Psychopharmacology (Berl) 2001, 156, 469–476. [Google Scholar]
  172. De Vries, T.J.; Schoffelmeer, A.N.; Binnekade, R.; Raaso, H.; Vanderschuren, L.J. Relapse to cocaine- and heroin-seeking behavior mediated by dopamine D2 receptors is time-dependent and associated with behavioral sensitization. Neuropsychopharmacology 2002, 26, 18–26. [Google Scholar]
  173. Domino, E.F. Nicotine induced behavioral locomotor sensitization. Prog. Neuropsychopharmacol. Biol. Psychiatry 2001, 25, 59–71. [Google Scholar] [CrossRef]
  174. Kalivas, P.W.; Duffy, P. Dopamine regulation of extracellular glutamate in the nucleus accumbens. Brain research. 1997, 761, 173–177. [Google Scholar] [CrossRef]
  175. Iyaniwura, T.T.; Wright, A.E.; Balfour, D.J. Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain. Psychopharmacology (Berl) 2001, 158, 73–79. [Google Scholar] [CrossRef]
  176. Balfour, D.J. The neurobiology of tobacco dependence: A preclinical perspective on the role of the dopamine projections to the nucleus accumbens [corrected]. Nicotine Tob. Res. 2004, 6, 899–912. [Google Scholar] [CrossRef]
  177. Kalivas, P.W.; Duffy, P. Effect of acute and daily neurotensin and enkephalin treatments on extracellular dopamine in the nucleus accumbens. J. Neurosci. 1990, 10, 2940–2949. [Google Scholar]
  178. Richelson, E.; Boules, M.; Fredrickson, P. Neurotensin agonists: Possible drugs for treatment of psychostimulant abuse. Life Sci. 2003, 73, 679–690. [Google Scholar]
  179. Fredrickson, P.; Boules, M.; Yerbury, S.; Richelson, E. Blockade of nicotine-induced locomotor sensitization by a novel neurotensin analog in rats. Eur. J. Pharmacol. 2003, 458, 111–118. [Google Scholar] [CrossRef]
  180. Fredrickson, P.; Boules, M.; Yerbury, S.; Richelson, E. Novel neurotensin analog blocks the initiation and expression of nicotine-induced locomotor sensitization. Brain Res. 2003, 979, 245–248. [Google Scholar] [CrossRef]
  181. Boules, M.; Oliveros, A.; Liang, Y.; Williams, K.; Shaw, A.; Robinson, J.; Fredrickson, P.; Richelson, E. A neurotensin analog, NT69L, attenuates intravenous nicotine self-administration in rats. Neuropeptides 2011, 45, 9–16. [Google Scholar] [CrossRef]
  182. Hall, F.S.; Centeno, M.; Perona, M.T.; Adair, J.; Dobner, P.R.; Uhl, G.R. Effects of neurotensin gene knockout in mice on the behavioral effects of cocaine. Psychopharmacology (Berl) 2012, 219, 35–45. [Google Scholar] [CrossRef]
  183. Krawczyk, M.; Mason, X.; DeBacker, J.; Sharma, R.; Normandeau, C.P.; Hawken, E.R.; di Prospero, C.; Chiang, C.; Martinez, A.; Jones, A.A.; et al. D1 dopamine receptor-mediated LTP at GABA synapses encodes motivation to self-administer cocaine in rats. J. Neurosci. 2013, 33, 11960–11971. [Google Scholar] [CrossRef]
  184. Felszeghy, K.; Espinosa, J.M.; Scarna, H.; Berod, A.; Rostene, W.; Pelaprat, D. Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference. Neuropsychopharmacology 2007, 32, 2601–2610. [Google Scholar] [CrossRef]
  185. Ramos-Ortolaza, D.L.; Negron, A.; Cruz, D.; Falcon, E.; Iturbe, M.C.; Cajigas, M.H.; Maldonado-Vlaar, C.S. Intra-accumbens shell injections of SR48692 enhanced cocaine self-administration intake in rats exposed to an environmentally-elicited reinstatement paradigm. Brain Res. 2009, 1280, 124–136. [Google Scholar]
  186. Torregrossa, M.M.; Kalivas, P.W. Neurotensin in the ventral pallidum increases extracellular gamma-aminobutyric acid and differentially affects cue- and cocaine-primed reinstatement. J. Pharmacol. Exp. Ther. 2008, 325, 556–566. [Google Scholar] [CrossRef]
  187. Gendron, L.; Perron, A.; Payet, M.D.; Gallo-Payet, N.; Sarret, P.; Beaudet, A. Low-Affinity Neurotensin Receptor (NTS2) Signaling: Internalization-Dependent Activation of Extracellular Signal-Regulated Kinases 1/2. Mol. Pharmacol. 2004, 66, 1421–1430. [Google Scholar] [CrossRef]
  188. Gruber, S.H.; Nomikos, G.G.; Mathe, A.A. d-Amphetamine-induced increase in neurotensin and neuropeptide Y outflow in the ventral striatum is mediated via stimulation of dopamine D1 and D2/3 receptors. J. Neurosci. Res. 2002, 69, 133–139. [Google Scholar] [CrossRef]
  189. Hertel, P.; Mathe, J.M.; Nomikos, G.G.; Iurlo, M.; Mathe, A.A.; Svensson, T.H. Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat. Behav. Brain Res. 1995, 72, 103–114. [Google Scholar] [CrossRef]
  190. Panayi, F.; Colussi-Mas, J.; Lambas-Senas, L.; Renaud, B.; Scarna, H.; Berod, A. Endogenous neurotensin in the ventral tegmental area contributes to amphetamine behavioral sensitization. Neuropsychopharmacology 2005, 30, 871–879. [Google Scholar] [CrossRef]
  191. Rompre, P.; Perron, S. Evidence for a role of endogenous neurotensin in the initiation of amphetamine sensitization. Neuropharmacology 2000, 39, 1880–1892. [Google Scholar] [CrossRef]
  192. Panayi, F.; Dorso, E.; Lambas-Senas, L.; Renaud, B.; Scarna, H.; Berod, A. Chronic blockade of neurotensin receptors strongly reduces sensitized, but not acute, behavioral response to D-amphetamine. Neuropsychopharmacology 2002, 26, 64–74. [Google Scholar] [CrossRef]
  193. Costa, F.G.; Frussa-Filho, R.; Felicio, L.F. The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioural sensitisation in mice. Eur. J. Pharmacol. 2001, 428, 97–103. [Google Scholar] [CrossRef]
  194. Feifel, D.; Melendez, G.; Murray, R.J.; Tina Tran, D.N.; Rullan, M.A.; Shilling, P.D. The reversal of amphetamine-induced locomotor activation by a selective neurotensin-1 receptor agonist does not exhibit tolerance. Psychopharmacology (Berl) 2008, 200, 197–203. [Google Scholar] [CrossRef]
  195. Fleckenstein, A.E.; Volz, T.J.; Riddle, E.L.; Gibb, J.W.; Hanson, G.R. New insights into the mechanism of action of amphetamines. Ann. Rev. Pharmacol. Toxicol. 2007, 47, 681–698. [Google Scholar] [CrossRef]
  196. Frankel, P.S.; Hoonakker, A.J.; Alburges, M.E.; McDougall, J.W.; McFadden, L.M.; Fleckenstein, A.E.; Hanson, G.R. Effect of methamphetamine self-administration on neurotensin systems of the basal ganglia. J. Pharmacol. Exp. Therapeut. 2011, 336, 809–815. [Google Scholar] [CrossRef]
  197. Wagstaff, J.D.; Gibb, J.W.; Hanson, G.R. Microdialysis assessment of methamphetamine-induced changes in extracellular neurotensin in the striatum and nucleus accumbens. J. Pharmacol. Exp. Ther. 1996, 278, 547–554. [Google Scholar]
  198. Frankel, P.S.; Alburges, M.E.; Bush, L.; Hanson, G.R.; Kish, S.J. Brain levels of neuropeptides in human chronic methamphetamine users. Neuropharmacology 2007, 53, 447–454. [Google Scholar] [CrossRef]
  199. Ehlers, C.L.; Somes, C.; Li, T.K.; Lumeng, L.; Kinkead, B.; Owens, M.J.; Nemeroff, C.B. Neurontensin studies in alcohol naive, preferring and non-preferring rats. Neuroscience 1999, 93, 227–236. [Google Scholar] [CrossRef]
  200. Li, Z.; Boules, M.; Richelson, E. NT69L blocks ethanol-induced increase of dopamine and glutamate levels in striatum of mouse. Neurosci. Lett. 2011, 487, 322–324. [Google Scholar] [CrossRef]
  201. Boules, M.; Fredrickson, P.; Richelson, E. Bioactive analogs of neurotensin. Peptides 2006, 27, 2523–2533. [Google Scholar] [CrossRef]
  202. American Pschiatric Association (Ed.) Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American Psychiatric Publishing: Arlington, VA, USA, 2013.
  203. Lam, K.S.; Bodfish, J.W.; Piven, J. Evidence for three subtypes of repetitive behavior in autism that differ in familiality and association with other symptoms. J. Child Psychol. Psychiatry Allied Discip. 2008, 49, 1193–1200. [Google Scholar] [CrossRef]
  204. Ghosh, A.; Michalon, A.; Lindemann, L.; Fontoura, P.; Santarelli, L. Drug discovery for autism spectrum disorder: Challenges and opportunities. Nat. Rev. Drug Discov. 2013, 12, 777–790. [Google Scholar] [CrossRef]
  205. Nemeroff, C.B.; Luttinger, D.; Hernandez, D.E.; Mailman, R.B.; Mason, G.A.; Davis, S.D.; Widerlov, E.; Frye, G.D.; Kilts, C.A.; Beaumont, K.; et al. Interactions of neurotensin with brain dopamine systems: Biochemical and behavioral studies. J. Pharmacol. Exp. Ther. 1983, 225, 337–345. [Google Scholar]
  206. Casanova, M.F.; Naidu, S.; Goldberg, T.E.; Moser, H.W.; Khoromi, S.; Kumar, A.; Kleinman, J.E.; Weinberger, D.R. Quantitative magnetic resonance imaging in Rett syndrome. J. Neuropsychiatry Clin. Neurosci. 1991, 3, 66–72. [Google Scholar]
  207. Reiss, A.L.; Abrams, M.T.; Greenlaw, R.; Freund, L.; Denckla, M.B. Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat. Med. 1995, 1, 159–167. [Google Scholar] [CrossRef]
  208. Harris, J.C.; Lee, R.R.; Jinnah, H.A.; Wong, D.F.; Yaster, M.; Bryan, R.N. Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome. Arch. Neurol. 1998, 55, 547–553. [Google Scholar] [CrossRef]
  209. Hollander, E.; Anagnostou, E.; Chaplin, W.; Esposito, K.; Haznedar, M.M.; Licalzi, E.; Wasserman, S.; Soorya, L.; Buchsbaum, M. Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol. Psychiatr. 2005, 58, 226–232. [Google Scholar] [CrossRef]
  210. Rojas, D.C.; Peterson, E.; Winterrowd, E.; Reite, M.L.; Rogers, S.J.; Tregellas, J.R. Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms. BMC Psychiatry 2006, 6, 56. [Google Scholar] [CrossRef]
  211. Hoeft, F.; Hernandez, A.; Parthasarathy, S.; Watson, C.L.; Hall, S.S.; Reiss, A.L. Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndrome. Hum. Brain Mapp. 2007, 28, 543–554. [Google Scholar] [CrossRef]
  212. Langen, M.; Schnack, H.G.; Nederveen, H.; Bos, D.; Lahuis, B.E.; de Jonge, M.V.; van Engeland, H.; Durston, S. Changes in the developmental trajectories of striatum in autism. Biol. Psychiatr. 2009, 66, 327–333. [Google Scholar] [CrossRef]
  213. Wolff, J.J.; Hazlett, H.C.; Lightbody, A.A.; Reiss, A.L.; Piven, J. Repetitive and self-injurious behaviors: Associations with caudate volume in autism and fragile X syndrome. J. Neurodev. Disord. 2013, 5, 12. [Google Scholar] [CrossRef]
  214. Ferraro, L.; Antonelli, T.; O’Connor, W.T.; Fuxe, K.; Soubrie, P.; Tanganelli, S. The striatal neurotensin receptor modulates striatal and pallidal glutamate and GABA release: Functional evidence for a pallidal glutamate-GABA interaction via the pallidal-subthalamic nucleus loop. J. Neurosci. 1998, 18, 6977–6989. [Google Scholar]
  215. Chen, L.; Yung, K.K.; Yung, W.H. Neurotensin depolarizes globus pallidus neurons in rats via neurotensin type-1 receptor. Neuroscience 2004, 125, 853–859. [Google Scholar] [CrossRef]
  216. Welch, J.M.; Lu, J.; Rodriguiz, R.M.; Trotta, N.C.; Peca, J.; Ding, J.D.; Feliciano, C.; Chen, M.; Adams, J.P.; Luo, J.; et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 2007, 448, 894–900. [Google Scholar] [CrossRef]
  217. El-Kordi, A.; Winkler, D.; Hammerschmidt, K.; Kastner, A.; Krueger, D.; Ronnenberg, A.; Ritter, C.; Jatho, J.; Radyushkin, K.; Bourgeron, T.; et al. Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism. Behav. Brain Res. 2013, 251, 41–49. [Google Scholar] [CrossRef]
  218. Greco, B.; Manago, F.; Tucci, V.; Kao, H.T.; Valtorta, F.; Benfenati, F. Autism-related behavioral abnormalities in synapsin knockout mice. Behav. Brain Res. 2013, 251, 65–74. [Google Scholar] [CrossRef]
  219. Uchino, S.; Waga, C. SHANK3 as an autism spectrum disorder-associated gene. Brain Dev. 2013, 35, 106–110. [Google Scholar] [CrossRef]
  220. Presti, M.F.; Lewis, M.H. Striatal opioid peptide content in an animal model of spontaneous stereotypic behavior. Behav. Brain Res. 2005, 157, 363–368. [Google Scholar] [CrossRef]
  221. Tanimura, Y.; King, M.A.; Williams, D.K.; Lewis, M.H. Development of repetitive behavior in a mouse model: Roles of indirect and striosomal basal ganglia pathways. Int. J. Dev. Neurosci. 2011, 29, 461–467. [Google Scholar] [CrossRef]
  222. Muehlmann, A.M.; Buchwald, Z.; Edington, G.; Lewis, M.H. Neuronal hypoactivation of the subthalamic nucleus in an inbred model of restricted, repetitive behavior. Available online: (accessed on 12 June 2014).
  223. Turner, C.A.; Lewis, M.H.; King, M.A. Environmental enrichment: Effects on stereotyped behavior and dendritic morphology. Dev. Psychobiol. 2003, 43, 20–27. [Google Scholar] [CrossRef]
  224. Tanimura, Y.; Vaziri, S.; Lewis, M.H. Indirect basal ganglia pathway mediation of repetitive behavior: Attenuation by adenosine receptor agonists. Behav. Brain Res. 2010, 210, 116–122. [Google Scholar] [CrossRef]
  225. Muehlmann, A.M.; Edington, G.; Mihalik, A.C.; Buchwald, Z.; Koppuzha, D.; Korah, M.; Lewis, M.H. Further characterization of repetitive behavior in C58 mice: Developmental trajectory and effects of environmental enrichment. Behav. Brain Res. 2012, 235, 143–149. [Google Scholar] [CrossRef]
  226. Ghanizadeh, A. Targeting neurotensin as a potential novel approach for the treatment of autism. J. Neuroinflammation. 2010, 7, 58. [Google Scholar] [CrossRef]
  227. Angelidou, A.; Francis, K.; Vasiadi, M.; Alysandratos, K.D.; Zhang, B.; Theoharides, A.; Lykouras, L.; Sideri, K.; Kalogeromitros, D.; Theoharides, T.C. Neurotensin is increased in serum of young children with autistic disorder. J. Neuroinflammation 2010, 7, 48. [Google Scholar] [CrossRef]
  228. Zhang, B.; Angelidou, A.; Alysandratos, K.D.; Vasiadi, M.; Francis, K.; Asadi, S.; Theoharides, A.; Sideri, K.; Lykouras, L.; Kalogeromitros, D.; et al. Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J. Neuroinflammation. 2010, 7, 80. [Google Scholar] [CrossRef]
  229. Koon, H.W.; Kim, Y.S.; Xu, H.; Kumar, A.; Zhao, D.; Karagiannides, I.; Dobner, P.R.; Pothoulakis, C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis. Proceed. Natl. Acad. Sci. USA. 2009, 106, 8766–8771. [Google Scholar]
  230. Li, X.; Chauhan, A.; Sheikh, A.M.; Patil, S.; Chauhan, V.; Li, X.M.; Ji, L.; Brown, T.; Malik, M. Elevated immune response in the brain of autistic patients. J. Neuroimmunol. 2009, 207, 111–116. [Google Scholar] [CrossRef]
  231. Adams, J.B.; Johansen, L.J.; Powell, L.D.; Quig, D.; Rubin, R.A. Gastrointestinal flora and gastrointestinal status in children with autism—Comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011, 11, 22. [Google Scholar] [CrossRef]
  232. Thomas, R.P.; Hellmich, M.R.; Townsend, C.M., Jr.; Evers, B.M. Role of gastrointestinal hormones in the proliferation of normal and neoplastic tissues. Endocr. Rev. 2003, 24, 571–599. [Google Scholar] [CrossRef]
  233. Kim, E.R.; Mizuno, T.M. Role of neurotensin receptor 1 in the regulation of food intake by neuromedins and neuromedin-related peptides. Neurosci. Lett. 2010, 468, 64–67. [Google Scholar] [CrossRef]
  234. Sharp, W.G.; Berry, R.C.; McCracken, C.; Nuhu, N.N.; Marvel, E.; Saulnier, C.A.; Klin, A.; Jones, W.; Jaquess, D.L. Feeding problems and nutrient intake in children with autism spectrum disorders: A meta-analysis and comprehensive review of the literature. J. Autism Dev. Disord. 2013, 43, 2159–2173. [Google Scholar] [CrossRef]
  235. Tordjman, S.; Anderson, G.M.; Botbol, M.; Brailly-Tabard, S.; Perez-Diaz, F.; Graignic, R.; Carlier, M.; Schmit, G.; Rolland, A.C.; Bonnot, O.; et al. Pain reactivity and plasma beta-endorphin in children and adolescents with autistic disorder. PloS One 2009, 4, e5289. [Google Scholar] [CrossRef]
  236. Wang, R.; Boules, M.; Gollatz, E.; Williams, K.; Tiner, W.; Richelson, E. Effects of 5 daily injections of the neurotensin-mimetic NT69L on the expression of neurotensin receptors in rat brain. Brain Res. Mol. Brain Res. 2005, 138, 24–34. [Google Scholar] [CrossRef]
  237. Perron, A.; Sharif, N.; Gendron, L.; Lavallee, M.; Stroh, T.; Mazella, J.; Beaudet, A. Sustained neurotensin exposure promotes cell surface recruitment of NTS2 receptors. Biochem. Biophys. Res. Commun. 2006, 343, 799–808. [Google Scholar] [CrossRef]
Back to TopTop