Repeated Administration of the Neurotensin Receptor Antagonist SR 48692 Differentially Regulates Mesocortical and Mesolimbic Dopaminergic Systems

Azzi, Mounia; Betancur, Catalina; Sillaber, Inge; Spanagel, Rainer; Rostène, William; Bérod, Anne

doi:10.1046/j.1471-4159.1998.71031158.x

Cited by 33 publications

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“…Ex vivo studies reported NT action on dopamine release in dopaminergic neurons (Brouard et al, 1994). Furthermore, our laboratory has previously demonstrated that in the nucleus accumbens and the mesencephalon, a chronic treatment with a NT-1 receptor antagonist increased TH expression with a loss of dopamine levels (Azzi et al, 1998). Under the same experimental conditions, NT-1 receptor antagonist treatment was also associated with a major increase of NT-1 receptor expression (Azzi et al, 1994).…”

Section: Discussionmentioning

confidence: 92%

“…The vast majority of the NT effects are mediated through a specific high-affinity NT receptor (NT-1 receptor), belonging to the G protein coupled receptor family (Tanaka et al, 1990). NT is very effective in enhancing [ decreased dopamine release in the nucleus accumbens and in the dopamine rich regions of the rat central nervous system (Azzi et al, 1998). Interestingly, NT acts equally well on TH expression and TH activity, because NT increases protein and mRNA in neuroblastoma cell lines (Najimi et al, 1998), and TH activity via a protein kinase C pathway in cultured tuberoinfundibular dopaminergic neurons (Berry and Gudelsky, 1992).…”

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confidence: 99%

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Neurotensin Induces Tyrosine Hydroxylase Gene Activation through Nitric Oxide and Protein Kinase C Signaling Pathways

et al. 2002

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The regulation of tyrosine hydroxylase (TH) represents an effective means to control the level of catecholamines, because TH is the major limiting enzyme of monoamine biosynthesis. The neuropeptide neurotensin (NT) is a neuromodulator of dopaminergic systems, and a direct interaction between NT and TH expression has been demonstrated in vivo and in vitro. In the present work, the molecular mechanisms and signaling pathways responsible for TH gene activation have been explored. In N1E-115 cells, NT agonist induced a TH protein level increase, correlating with a significant increase in TH mRNA abundance. This cellular response was the result of TH promoter activation, via c-fos and Jun D binding at the AP-1 responsive element. Using selective protein kinase C and nitric oxide synthase inhibitors, we demonstrate, by quantitative reverse transcription-polymerase chain reaction, gel shift, and protein assays, that TH gene activation by NT agonist requires both protein kinase C stimulation and nitric oxide production. The two pathways exert distinct roles; whereas nitric oxide synthase inhibitors blocked c-fos expression, protein kinase C inhibitors blocked that of Jun D. The requirement for two distinct and concomitant pathways by NT demonstrates a very fine level of control of specificity on TH gene activation.Tyrosine hydroxylase (TH) is the first and major ratelimiting enzyme of catecholamine biosynthesis in dopaminergic and noradrenergic neurons (Nagatsu et al., 1964). These neurons are involved in the regulation of several important brain functions including motor activity, stress, and emotional responses. A crucial role for this enzyme has been demonstrated in diseases caused by central dopaminergic neuronal damage, such as Parkinson disease, schizophrenia, or prolactinemia (Mallet, 1996;Haavik and Toska, 1998). TH regulation is generated when dopaminergic and noradrenergic systems are altered by a variety of factors induced by pharmacological, environmental, or physiological changes. This regulation affects TH activity through phosphorylation, which modulates both enzyme affinity for cofactor and maximal velocity (Kumer and Vrana, 1996). Additionally, TH protein levels can also be modulated by alterations in TH gene transcription or TH mRNA stability (Kumer and Vrana, 1996). Heterologous TH regulation has also been described in particular through peptidergic neurotransmitters (Haycock, 1996). Despite the accumulation of evidence detailing the direct role of the second messenger cascades associated to G proteins in TH phosphorylation and TH gene stimulation, the elucidation of the overall intracellular mechanism remains fragmentary for each of the specific molecules leading to TH gene regulation.Neurotensin (NT) is a 13-amino-acid peptide and is colocalized with TH in dopaminergic neurons of the hypothalamus, and mesencephalom (Hokfelt et al., 1984). Many studies have established diverse regulatory effects exerted by NT on dopaminergic systems (Berod and Rostene, 2002). The vast majority of the NT effec...

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Neurotensin Induces Tyrosine Hydroxylase Gene Activation through Nitric Oxide and Protein Kinase C Signaling Pathways

et al. 2002

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“…Chronic administration of SR-48692, which is a nonpeptide and a high-affinity NT 1 receptor antagonist with agonist activity at NT 2 receptors, can decrease methamphetamine-induced dopamine release in the nucleus accumbens, 340 suggesting this compound could also have antipsychotic-like effects.…”

Section: Noradrenergic Agentsmentioning

confidence: 99%

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

et al. 2004

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The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

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“…Microinjection of NT into the VTA, produces a dose-dependent in vivo DA release in the nucleus accumbens and also causes a dose-dependent circling behavior (Steinberg et al 1995). Moreover, blockade of NT receptors by the NT receptor antagonist SR 48692 decreases basal extracellular levels of DA and its metabolites in the nucleus accumbens, suggesting that NT modulates the mesolimbic DA system (Azzi et al 1998). Neurotensin has also been shown to mimic the effects of neuroleptic drugs in behavioral models of antipsychotic drug action.…”

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Effects of Haloperidol and Risperidone on Neurotensin Levels in Brain Regions and Neurotensin Efflux in the Ventral Striatum of the Rat

Gruber

Nomikos

Mathé

2002

Neuropsychopharmacology

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Neurotensin (NT) may play a role in the pathophysiology of schizophrenia and in the mechanism of action of antipsychotic drugs. Here we studied the effects of a 30-day regimen of haloperidol (1.15 mg/100 g food) and risperidone (1.15 and 2.3 mg/100 g food) on NT-like immunoreactivity (-LI) levels in brain tissue and NT-LI efflux in the ventral striatum (VSTR) of the rat. Haloperidol, but not risperidone, increased NT-LI levels in the striatum. In the occipital cortex, risperidone, but not haloperidol, decreased levels of NT-LI. In the hippocampus and the frontal cortex both haloperidol and risperidone (the higher dose) increased NT-LI levels. In the VSTR, haloperidol and risperidone (the higher dose) decreased NT-LI efflux and abolished the stimulatory effect of d-amphetamine (1.5 mg/kg, s.c.). Thus, changes in NT occur in response toNeurotensin (NT) is a 13-amino acid peptide originally isolated from hypothalamus (Carraway and Leeman 1973). Several anatomical, behavioral and pharmacological studies have demonstrated an interaction between NT and dopamine (DA) in the central nervous system (CNS). For example, high levels of NT and its binding sites have been found in both the cell body regions, i.e. the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA), as well as the major projection areas of the ascending dopaminergic pathways, i.e. the striatum and the nucleus accumbens (Kasckow and Nemeroff 1991;Lambert et al. 1995; Quirion 1983). Within both the VTA and the SN, NT immunoreactive fibers are found in close proximity to DA cell bodies (Hökfelt et al. 1984); within the VTA, NT is colocalized with DA (Hökfelt et al. 1984;Kalivas 1993), while in the striatal complex, the majority of the NT binding sites in rat are located on DA terminals (Cadet et al. 1991). There exists substantial pharmacological evidence showing that NT is involved in the regulation of DA neurotransmission. For example, local perfusion with NT dose-dependently increases striatal extracellular DA levels without affecting DA metabolite levels and modifies the inhibitory effects of DA-D 1 and DA-D 2 receptor agonists on striatal DA release (Fuxe et al. 1992). In contrast to the striatum, in the nucleus accumbens direct infu- NO . 5 sion of NT does not affect extracellular DA levels, but increases extracellular levels of the DA metabolite homovanillic acid (Chapman et al. 1992). Microinjection of NT into the VTA, produces a dose-dependent in vivo DA release in the nucleus accumbens and also causes a dose-dependent circling behavior (Steinberg et al. 1995). Moreover, blockade of NT receptors by the NT receptor antagonist SR 48692 decreases basal extracellular levels of DA and its metabolites in the nucleus accumbens, suggesting that NT modulates the mesolimbic DA system (Azzi et al. 1998). Neurotensin has also been shown to mimic the effects of neuroleptic drugs in behavioral models of antipsychotic drug action. Thus, centrally injected NT antagonizes psychostimulant-induced locomotor hyperactivity (Ervin et al. 1981;Joli...

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Repeated Administration of the Neurotensin Receptor Antagonist SR 48692 Differentially Regulates Mesocortical and Mesolimbic Dopaminergic Systems

Cited by 33 publications

References 50 publications

Neurotensin Induces Tyrosine Hydroxylase Gene Activation through Nitric Oxide and Protein Kinase C Signaling Pathways

Neurotensin Induces Tyrosine Hydroxylase Gene Activation through Nitric Oxide and Protein Kinase C Signaling Pathways

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

Effects of Haloperidol and Risperidone on Neurotensin Levels in Brain Regions and Neurotensin Efflux in the Ventral Striatum of the Rat

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