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

Boules, Mona; Fredrickson, Paul A.; Muehlmann, Amber M.; Richelson, Elliott

doi:10.3390/bs4020125

Cited by 37 publications

(31 citation statements)

References 223 publications

(225 reference statements)

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“…Nts administration within the VTA mimics some effects of psychostimulant treatment, including promoting self-administration, hyperactivity and DA release to the NAc, as well as generating a conditioned place preference and locomotor sensitization [56,70,73]. Conversely, Nts in the NAc abrogates amphetamine-induced locomotion as well as “rewarding” VTA electrical self-stimulation [73,84]. At face value, these findings suggest diverging roles for Nts to promote psychostimulant reward via the VTA, or to suppress it via the NAc.…”

Section: Physiology Regulated By Central Nts Signalingmentioning

confidence: 99%

“…However, addiction is a complex and incompletely understood process, often producing different acute and chronic adaptations to neural circuitry that have yet to be disentangled. The role of Nts in addiction is similarly complex, such that Nts-NtsR1 signaling has been contradictorily implicated in promoting drug abuse as well as in attenuating it [70,73,82,83]. Thus, while Nts is well established to engage DA signaling systems that contribute to drug intake, there is currently no consensus view on how Nts modifies the system to regulate drug seeking or addiction.…”

Section: Physiology Regulated By Central Nts Signalingmentioning

confidence: 99%

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Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

Schroeder

Leinninger

2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The peptide neurotensin (Nts) was discovered within the brain over 40 years ago and is implicated in regulating analgesia, body temperature, blood pressure, locomotor activity and feeding. Recent evidence suggests, however, that these disparate processes may be controlled via specific populations of Nts neurons and receptors. The neuronal mediators of Nts anorectic action are now beginning to be understood, and, as such, modulating specific Nts pathways might be useful in treating feeding and body weight disorders. This review considers mechanisms through which Nts normally regulates feeding and how disruptions in Nts signaling might contribute to the disordered feeding and body weight of schizophrenia, Parkinson’s disease, anorexia nervosa, and obesity. Defining how Nts specifically mediates feeding vs. other aspects of physiology will inform the design of therapeutics that modify body weight without disrupting other important Nts-mediated physiology.

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Section: Physiology Regulated By Central Nts Signalingmentioning

confidence: 99%

Section: Physiology Regulated By Central Nts Signalingmentioning

confidence: 99%

Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

Schroeder

Leinninger

2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In contrast, the caudal “tail” of the VTA that forms a continuum with the rostromedial tegmental nucleus (RMTg) is enriched with GABA-ergic neurons, which inhibit VTA DA neurons and serve as negative regulators of DA-mediated behaviors (Carr and Sesack, 2000; Margolis et al, 2012; Tan et al, 2012; van Zessen et al, 2012). Given that alterations in both VTA DA and Nts signaling have been implicated in the pathogenesis of drug addiction, depression, anxiety, schizophrenia, autism, pain processing and obesity, there is likely functional overlap of these systems (Boules et al, 2014; Caceda et al, 2012; Carey et al, 2017; Ellenbroek et al, 2016; Ferraro et al, 2016; Fitzpatrick et al, 2012; Howes et al, 2017; Kim and Mizuno, 2010; Li et al, 2016; Nestler and Carlezon Jr, 2006; Rothwell, 2016; Theoharides et al, 2016; Volkow et al, 2013). It is therefore critical to define the precise neural mechanisms by which Nts engages the VTA, to understand how it regulates such diverse physiology and how Nts signaling becomes maladaptive in disease.…”

Section: Introductionmentioning

confidence: 99%

Determination of neurotensin projections to the ventral tegmental area in mice

et al. 2018

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Pharmacologic treatment with the neuropeptide neurotensin (Nts) modifies motivated behaviors such as feeding, locomotor activity, and reproduction. Dopamine (DA) neurons of the ventral tegmental area (VTA) control these behaviors, and Nts directly modulates the activity of DA neurons via Nts receptor-1. While Nts sources to the VTA have been described in starlings and rats, the endogenous sources of Nts to the VTA of mice remain incompletely understood, impeding determination of which Nts circuits orchestrate specific behaviors in this model. To overcome this obstacle we injected the retrograde tracer Fluoro-Gold into the VTA of mice that express GFP in Nts neurons. Identification of GFP-Nts cells that accumulate Fluoro-Gold revealed the Nts afferents to the VTA in mice. Similar to rats, most Nts afferents to the VTA of mice arise from the medial and lateral preoptic areas (POA) and the lateral hypothalamic area (LHA), brain regions that are critical for coordination of feeding and reproduction. Additionally, the VTA receives dense input from Nts neurons in the nucleus accumbens shell (NAsh) of mice, and minor Nts projections from the amygdala and periaqueductal gray area. Collectively, our data reveal multiple populations of Nts neurons that provide direct afferents to the VTA and which may regulate specific aspects of motivated behavior. This work lays the foundation for understanding endogenous Nts actions in the VTA, and how circuit-specific Nts modulation may be useful to correct motivational and affective deficits in neuropsychiatric disease.

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“…NT receptor antagonists were demonstrated to inhibit the therapeutic-like effects of antipsychotics on disruptions in prepulse inhibition (PPI) and amphetamine-induced hyperlocomotion in rodents [13, 14]. Furthermore, NT analogs have been shown to suppress psychomotor agitation and disruptions in PPI without causing extrapyramidal side effects, indicating that the effects of NT analogs more closely resemble that of atypical antipsychotics [15, 16]. Genetic and pharmacological manipulations suggest that NTS1 may mediate the antipsychotic-like effects of NT [17–19].…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic-like effects of a neurotensin receptor type 1 agonist

Vadnie

Ayers-Ringler

Oliveros

et al. 2016

Behavioural Brain Research

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Although neurotensin (NT) analogs are known to produce antipsychotic-like effects, the therapeutic possibility of a brain penetrant NTS1 agonist in treating psychiatric disorders has not been well studied. Here, we examined whether PD149163, a brain-penetrant NTS1-specific agonist, displays antipsychotic-like effects in C57BL/6J mice by investigating the effect of PD149163 on amphetamine-mediated hyperactivity and amphetamine-induced disruption of prepulse inhibition. In addition, we assessed the effect of PD149163 on glycogen synthase kinase-3 (GSK-3) activity, a downstream molecular target of antipsychotics and mood stabilizers, using phospho-specific antibodies. PD149163 (0.1 and 0.5 mg/kg) inhibited amphetamine-induced hyperactivity in mice, indicating that NTS1 activation inhibits psychomotor agitation. PD149163 (0.5 mg/kg) also increased prepulse inhibition, suggesting that NTS1 activation reduces prepulse inhibition deficits which often co-occur with psychosis in humans. Interestingly, PD149163 increased the inhibitory serine phosphorylation on both GSK-3α and GSK-3β in a dose- and time-dependent manner in the nucleus accumbens and medial prefrontal cortex of the mice. Moreover, PD149163 inhibited GSK-3 activity in the nucleus accumbens and medial prefrontal cortex in the presence of amphetamine. Thus, like most current antipsychotics and mood stabilizers, PD149163 inhibited GSK-3 activity in cortico-striatal circuitry. Together, our findings indicate that PD149163 may be a novel antipsychotic.

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

Cited by 37 publications

References 223 publications

Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

Determination of neurotensin projections to the ventral tegmental area in mice

Antipsychotic-like effects of a neurotensin receptor type 1 agonist

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