Neurotensin: Role in psychiatric and neurological diseases

Cáceda, Ricardo; Kinkead, Becky; Nemeroff, Charles B.

doi:10.1016/j.peptides.2006.04.024

Cited by 110 publications

(99 citation statements)

References 280 publications

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“…NT receptor ligands have attracted much attention as possible new antipsychotic drug candidates (58 -60). It has been argued that antipsychotic-like effects of NT could be caused specifically by a reduction in D2R-mediated neurotransmission in the accumbens through a combina-tion of pre-and postsynaptic effects (1,59,61). Our finding of a differential ability of NT to regulate D2S and D2L internalization is most relevant in this context because it provides a new framework to explain how NT may differentially regulate presynaptic and postsynaptic D2Rs.…”

Section: Discussionmentioning

confidence: 65%

Neurotensin Triggers Dopamine D2 Receptor Desensitization through a Protein Kinase C and β-Arrestin1-dependent Mechanism

Thibault

Albert

Piñeyro

et al. 2011

Journal of Biological Chemistry

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The peptide neurotensin (NT) is known to exert a potent excitatory effect on the dopaminergic system by inhibiting D2 dopamine (DA) receptor (D2R) function. This regulation is dependent on activation of PKC, a well known effector of the type 1 NT receptor (NTR1). Because PKC phosphorylation of the D2R has recently been shown to induce its internalization, we hypothesized that NT acts to reduce D2R function through heterologous desensitization of the D2R. In the present study, we first used HEK-293 cells to demonstrate that NT induces PKC-dependent D2R internalization. Furthermore, internalization displayed faster kinetics in cells expressing the D2R short isoform, known to act as an autoreceptor in DA neurons, than in cells expressing the long isoform, known to act as a postsynaptic D2R. In patch clamp experiments on cultured DA neurons, overexpression of a mutant D2S lacking three key PKC phosphorylation sites abrogated the ability of NT to reduce D2R-mediated cell firing inhibition. Short interfering RNA-mediated inhibition of ␤-arrestin1 and dynamin2, proteins important for receptor desensitization, reduced agonist-induced desensitization of D2R function, but only the inhibition of ␤-arrestin1 reduced the effect of NT on D2R function. Taken together, our data suggest that NT acutely regulates D2 autoreceptor function and DA neuron excitability through PKC-mediated phosphorylation of the D2R, leading to heterologous receptor desensitization.Since its discovery in the 1970s, NT 2 has been well established as a potent modulator of the DA system (1, 2). A vast majority of DA neurons in the substantia nigra and the ventral tegmental area express NTR1, the high affinity NT receptor (3, 4). Activation of these G␣ q -coupled receptors has been shown to increase DA neuron excitability via distinct mechanisms, one of which consists in a reduction of presynaptic D2 autoreceptor function (5-8). Activation of these D2Rs by DA normally causes cell hyperpolarization, which leads to a decrease in both spontaneous firing and DA release (9 -13). D2R regulation is an important area of interest for modern neuropharmacology because all clinically effective antipsychotic drugs (APDs) act at least in part as D2R antagonists. Moreover, because a growing amount of data from both human and animal studies provides evidence for the implication of NT in the pathophysiology of schizophrenia and in the action of APDs (14 -22), a better understanding of the mechanism mediating the NTR1-D2R interaction seems necessary.The major second messenger cascade triggered by NTR1 signaling involves activation of phospholipase C and the subsequent increase in intracellular calcium concentration, inositoltriphosphate production, and PKC activity, all of which have been linked to physiological effects of NT (7,(23)(24)(25)(26). We have previously demonstrated that the regulation of D2R function by NT in cultured DA neurons requires PKC activity (27). Interestingly, it was also shown that the D2R can be directly phosphorylated by PKC, leading to agonist-i...

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Section: Discussionmentioning

confidence: 65%

Neurotensin Triggers Dopamine D2 Receptor Desensitization through a Protein Kinase C and β-Arrestin1-dependent Mechanism

Thibault

Albert

Piñeyro

et al. 2011

Journal of Biological Chemistry

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“…Cocaine is well established to increase the extracellular concentration of dopamine by inhibiting dopamine transporters (Seiden et al, 1993), and an interaction between NT and dopamine is anatomically supported by the fact that NT is colocalized with dopamine in projection neurons in the VTA and that the VTA projects to the VP (Bayer et al, 1991;Klitenick et al, 1992). However, the literature on this colocalized projection shows a mixed interaction between NT and dopamine (Cá ceda et al, 2006). Thus, although neurotensin administered in the VTA enhances dopamine release in the NAc (Kalivas and Duffy, 1990;Laitinen et al, 1990), the NT antagonist SR48692 enhances methamphetamine-induced dopamine release in the NAc (Wagstaff et al, 1994), and low doses of neurotensin in the NAc decrease dopamine release (Tanganelli et al, 1994).…”

mentioning

confidence: 99%

Neurotensin in the Ventral Pallidum Increases Extracellular γ-Aminobutyric Acid and Differentially Affects Cue- and Cocaine-Primed Reinstatement

Torregrossa

Kalivas²

2008

J Pharmacol Exp Ther

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Cocaine-primed reinstatement is an animal model of drug relapse. The neurocircuitry underlying cocaine-primed reinstatement includes a decrease in GABA in the ventral pallidum (VP) that is inhibited by a opioid receptor antagonist, suggesting that opioid peptides colocalized with GABA in the projection from the nucleus accumbens to the VP may mediate this effect. Neurotensin is also colocalized with GABA and has been shown to increase GABA release in several brain regions. Therefore, the present study determined whether neurotensin increases GABA release in the VP, antagonizes cocaine-induced decreases in GABA, and prevents reinstatement of cocaine seeking. In vivo microdialysis revealed that the neurotensin agonist neurotensin peptide fragment 8 -13 [NT(8 -13)] increased GABA in the VP in a neurotensin receptor and tetrodotoxin-dependent manner and blocked the cocaine-induced decrease in GABA. NT(8 -13) (3 nmol) microinjected into the VP prevented cue-induced reinstatement without affecting cocaine self-administration. In contrast, 3 nmol NT(8 -13) potentiated cocaine-primed reinstatement. The3.1.13,7]decane-2-carboxylic acid) had no effect on any behavioral measure when infused in the VP at the dose tested but attenuated cocaine-primed reinstatement when administered systemically. In contrast to reinstatement, NT(8 -13) did not alter the motor response to acute cocaine or the development of motor sensitization by chronic cocaine. Three conclusions can be drawn from these data: 1) neurotensin promotes GABA release in the VP and correspondingly inhibits cue-induced reinstatement, 2) neurotensin and cocaine interact in a manner that countermands the neurotensin-induced increase in GABA and promotes reinstatement, and 3) endogenous release of neurotensin in the VP is not necessary for reinstatement.Drug addiction is a serious public health issue, and one of the most problematic aspects of addiction is the tendency to relapse even after extended periods of abstinence. Relapse can be studied in rodents using a combination of neurochemical and behavioral methods, including reinstatement of drug seeking. In this model, animals are trained to self-administer a drug of abuse, this behavior is then extinguished by removal of the reinforcer, and then drug seeking is reinstated by exposure to a stressor, drug-associated cue, or the drug itself (Shalev et al

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“…150 Indeed, significant preclinical data suggested a potential use of NT receptor agonists as novel therapeutic agents for the treatment of schizophrenia. 150 For example, administration of NT agonists, such as PD-149163, can reverse amphetamine-induced effects on hyperactivity and prepulse inhibition without inducing catalepsy. 151 Thus, NT receptor agonists likely have potential in the treatment of schizophrenia; however, there have been no published clinical trials of NT agonists.…”

Section: Neurotensin Receptorsmentioning

confidence: 99%

“…Interestingly, there is also seemingly contradictory evidence indicating that NT antagonists may have antipsychotic potential as there may be pathologically increased NT tone in schizophrenia. 150 A recent clinical trial, however, showed no antipsychotic efficacy of a potent and selective NT 1 receptor antagonist, SR-48692, compared with placebo. 81 Thus, NT antagonists may not be useful for the treatment of schizophrenia; however, clinical trials of NT agonists are needed to explore this novel treatment strategy for schizophrenia.…”

Section: Neurotensin Receptorsmentioning

confidence: 99%

The pipeline and future of drug development in schizophrenia

2007

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While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.

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Neurotensin: Role in psychiatric and neurological diseases

Cited by 110 publications

References 280 publications

Neurotensin Triggers Dopamine D2 Receptor Desensitization through a Protein Kinase C and β-Arrestin1-dependent Mechanism

Neurotensin Triggers Dopamine D2 Receptor Desensitization through a Protein Kinase C and β-Arrestin1-dependent Mechanism

Neurotensin in the Ventral Pallidum Increases Extracellular γ-Aminobutyric Acid and Differentially Affects Cue- and Cocaine-Primed Reinstatement

The pipeline and future of drug development in schizophrenia

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