Neurotensin-induced modulation of dopamine D2 receptors and their function in rat striatum: Counteraction by a NTR1-like receptor antagonist

Dı́az-Cabiale, Zaida; Fuxé, Kjell; Narváez, José Ángel; Finetti, Simone; Antonelli, Tiziana; Tanganelli, Sergio; Ferraro, Luca

doi:10.1097/00001756-200205070-00006

Cited by 35 publications

(26 citation statements)

References 22 publications

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“…Our electrophysiological data suggest that NT causes acute heterologous desensitization of presynaptic D2R through a PKCand ␤-arr1-dependent mechanism. Numerous reports have shown that NT can also negatively regulate postsynaptic D2R function in the striatum and other brain regions (55,(63)(64)(65). As suggested by our present results, it is possible that NT regulates pre-and postsynaptic D2Rs via a similar heterologous desensitization mechanism, but with different magnitudes and time courses.…”

Section: Discussionsupporting

confidence: 67%

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: Discussionsupporting

confidence: 67%

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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“…Recent work also indicates that there are extensive NT inputs to the VTA [178], and AMP-evoked NT release in this region could also modulate local neurotransmitter release, although such release has not been demonstrated. NT activation of dopamine neurons would seem to be unlikely to be involved in augmenting dopamine release since AMP releases dopamine from non-vesicular stores by promoting reverse transport through the dopamine transporter [179], although as mentioned above NT could augment AMP stimulation of dopamine release through attenuation of D 2 autoreceptor signaling [169,170,180].…”

Section: Nt Modulation Of Psychostimulant Responsesmentioning

confidence: 97%

“…62,2005 Review Article 1953 NMDA receptor signaling, suggesting that NT is released from D 1 -positive neurons [167,168]. NT could influence AMP-stimulated outflow of dopamine through a dampening of D 2 receptor-mediated autoinhibition [169], since this process reportedly modulates AMPevoked dopamine release [170]. NT microinjection in the striatum also increases glutamate release [100,171], suggesting that local NT release could augment glutamate signaling, as argued above for APD responses.…”

Section: Nt Modulation Of Psychostimulant Responsesmentioning

confidence: 99%

“…These data suggest that NT influences striatal activation principally through effects on either nigral or cortical striatal afferents. NT has been shown to antagonize D 2 autoreceptor function and could enhance amphetamine-evoked increases in extracellular dopamine levels through antagonism of D 2 autoinhibition under certain circumstances [169,170]. Intrastriatal NT administration has also been shown to increase glutamate release through NTR-1 [100,101].…”

Section: Nt Facilitates Nociceptive Responses and Is Required For Strmentioning

confidence: 99%

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Multitasking with neurotensin in the central nervous system

Dobner

2005

Cell. Mol. Life Sci.

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The 13-amino acid peptide neurotensin (NT) was discovered over 30 years ago and has been implicated in a wide variety of neurotransmitter and endocrine functions. This review focuses on four areas where there has been substantial recent progress in understanding NT signaling and several functions of the endogenous peptide. The first area concerns the functional activation of the high-affinity NT receptor, NTR-1, including the delineation of the NT binding pocket and receptor domains involved in functional coupling to intracellular signaling pathways. The development of NT receptor antagonists and the application of genetic and molecular genetic approaches have accelerated progress in understanding NT function in several areas, including the involvement of NT in antipsychotic drug actions, psychostimulant sensitization and the modulation of pain, and these are reviewed in that order. There is now substantial evidence indicating that NT is required for certain antipsychotic drug actions and that the peptide plays a key role in stress-induced analgesia.

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“…The mode of Ntsr1-DA receptor interaction varies with cells and brain regions. For example, in striatal neurons, NT suppresses presynaptic D 2 -like autoreceptors, which results in an increased level of extracellular DA (Diaz-Cabiale et al, 2002;Ferraro et al, 1997). Notably, Ntsr1 decreases the agonist-binding affinity of D 2 -like receptors via allosteric Ntsr1-D 2 -like receptor interactions (Diaz-Cabiale et al, 2002;von Euler et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Heightened Amygdala Long-Term Potentiation in Neurotensin Receptor Type-1 Knockout Mice

Amano

Wada

Yamada

et al. 2008

Neuropsychopharmacol

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Neurotensin receptor type-1 (Ntsr1) is the main receptor subtype that underlies neurotensin (NT)-mediated modulation of the dopamine (DA) system. Although NT and DA coexist in the basolateral nucleus of the amygdala (BLA), the function of Ntsr1 in the amygdala is not well characterized. In the present study, we utilized Ntsr1 knockout (Ntsr1-KO) mice to examine the role of Ntsr1 in the amygdala. In acute brain slices of Ntsr1-KO mice, synaptic currents elicited in BLA pyramidal neurons by electrical stimulation of the lateral nucleus of the amygdala (LA) were greatly potentiated by tetanic stimulation (BLA-long-term potentiation (LTP)). Such potentiation was not evident in pyramidal neurons of wild-type mice. In the presence of an antagonist of Ntsr1, SR48692, BLA-LTP was consistently observed in the neurons of wild-type mice, suggesting that both inherited deletion and acute pharmacological blockade of Ntsr1 induce BLA-LTP. BLA-LTP in Ntsr1-KO mice was impaired by sulpiride, a DA D 2 -like receptor antagonist. Conversely, quinpirole, a D 2 -like receptor agonist, induced pronounced BLA-LTP in wild-type mice, suggesting the upregulation of D 2 -like receptor activity in Ntsr1-KO mice. The ratio of NMDA receptor-mediated to non-NMDA receptor-mediated synaptic currents in Ntsr1-KO mouse BLA neurons was approximately double that measured in wild-type mouse neurons. Furthermore, quinpirole potentiated NMDA receptormediated synaptic currents in the BLA of wild-type mice. These results suggest that, without Ntsr1, synaptic responses from the LA to BLA pyramidal neurons undergo LTP in response to tetanus stimulation through facilitation of D 2 -like receptor-induced activation of NMDA receptors.

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Neurotensin-induced modulation of dopamine D2 receptors and their function in rat striatum: Counteraction by a NTR1-like receptor antagonist

Cited by 35 publications

References 22 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

Multitasking with neurotensin in the central nervous system

Heightened Amygdala Long-Term Potentiation in Neurotensin Receptor Type-1 Knockout Mice

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