Neurotensin receptor type 1 regulates ethanol intoxication and consumption in mice

Lee, Moonnoh R.; Hinton, David J.; Song, Jane Y.; Lee, Kyungwon; Choo, C. Richard; Johng, Heidi; Unal, Sencan S.; Richelson, Elliott; Choi, Doo Sup

doi:10.1016/j.pbb.2010.01.012

Cited by 37 publications

(45 citation statements)

References 39 publications

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“…This is interesting since rodents have been reported to develop rapid tolerance to some effects of NT agonists (such as hypothermia), but do not develop tolerance to the antipsychotic-like effects of NT (Boules et al, 2003; Feifel et al, 2008; Hadden et al, 2005). There is also interest in developing drugs targeting the NT system for the treatment of addiction, especially for alcohol use disorders (Lee et al, 2010). In future studies, it will be important to explore whether repeated administration of PD149163 in mice reduces alcohol drinking or schizophrenia-like behavior with minimal locomotor side effects.…”

Section: Discussionmentioning

confidence: 99%

Activation of neurotensin receptor type 1 attenuates locomotor activity

et al. 2014

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Intracerebroventricular administration of neurotensin (NT) suppresses locomotor activity. However, the brain regions that mediate the locomotor depressant effect of NT and receptor subtype-specific mechanisms involved are unclear. Using a brain-penetrating, selective NT receptor type 1 (NTS1) agonist PD149163, we investigated the effect of systemic and brain region-specific NTS1 activation on locomotor activity. Systemic administration of PD149163 attenuated the locomotor activity of C57BL/6J mice both in a novel environment and in their homecage. However, mice developed tolerance to the hypolocomotor effect of PD149163 (0.1 mg/kg, i.p.). Since NTS1 is known to modulate dopaminergic signaling, we examined whether PD149163 blocks dopamine receptor-mediated hyperactivity. Pretreatment with PD149163 (0.1 or 0.05 mg/kg, i.p.) inhibited D2R agonist bromocriptine (8 mg/kg, i.p.)-mediated hyperactivity. D1R agonist SKF81297 (8 mg/kg, i.p.)-induced hyperlocomotion was only inhibited by 0.1 mg/kg of PD149163. Since the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in the behavioral effects of NT, we examined whether microinjection of PD149163 into these regions reduces locomotion. Microinjection of PD149163 (2 pmol) into the NAc, but not the mPFC suppressed locomotor activity. In summary, our results indicate that systemic and intra-NAc activation of NTS1 is sufficient to reduce locomotion and NTS1 activation inhibits D2R-mediated hyperactivity. Our study will be helpful to identify pharmacological factors and a possible therapeutic window for NTS1-targeted therapies for movement disorders.

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Section: Discussionmentioning

confidence: 99%

Activation of neurotensin receptor type 1 attenuates locomotor activity

et al. 2014

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“…NT69L is a neurotensin receptor agonist that attenuates nicotine self-administration in rats [15] and alcohol consumption in mice [18]. NT69L works by interacting with the common neurotransmitter circuits supporting the rewarding process for both nicotine and alcohol.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic administration of NT69L reduces alcohol preference and consumption in mice through modulation of the NTS1 [18]. Biochemically, NT69L normalizes the nicotine-induced changes in DA [19], the neurotransmitter that promotes the motivational process for both nicotine and alcohol, and the alcohol-induced increase in DA and glutamate in the striatum [20].…”

Section: Introductionmentioning

confidence: 98%

Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats

Boules¹,

Stennett²,

Muhktar³

et al. 2013

J Addict Res Ther

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IntroductionNicotine and alcohol addiction are frequently co-morbid problems [1]. The co-dependence of nicotine and alcohol addiction complicates treatment and is often associated with significant morbidity and mortality. Prevalence of smoking in alcoholics is as high as 90% compared to 30% for the general population [2] and alcohol consumption is associated with high nicotine use [3,4]. Co-morbid cigarette smoking and alcoholism has been associated with higher rates of depression in comparison with non-alcoholic smokers [5] and increased cravings for nicotine in comparison with non alcohol dependent smokers [6]. Additionally, smoker alcoholics are more likely to die from smoking related diseases rather than directly from an alcohol related medical condition [7]. Pharmacotherapeutic options for the treatment of alcohol and tobacco co-dependence are limited. Thus, there is a critical need for the development of novel drugs implementing new therapeutic targets.Neurotensin (NT) is a neuropeptide that is closely associated with, and modulates dopamine (DA) [8], acetylcholine (ACh), glutamate, and γ-aminobutyric acid (GABA) neurotransmission, all of which are involved in addiction and reward pathways. Local administration of NT in the prefrontal cortex (PFC) increases extracellular levels of ACh and GABA [9]. Similar data were obtained with the extracranial injection of the NT agonist NT69L [10], a compound that was developed in our laboratory. NT also enhances GABAergic activity in rat hippocampus [11] and reduces glutamatergic neurotransmission in dorsolateral striatum [12]. However, NT must be administered centrally to have an effect because it is easily degraded by peptidases. Our laboratory has developed many NT agonists that can be administered extracranially and mimic the central effects of NT. The most studied of these agonists is NT69L, which binds with equal affinity to the two well-characterized NT receptors, subtype 1 (NTS1) and subtype 2 (NTS2). Our work with NT69L shows that it blocks nicotine-induced sensitization and nicotine self-administration [13][14][15].In addition to its role in animal models for nicotine addiction, the NT system has been strongly implicated in the neurochemical and behavioral effects of alcohol use [16,17]. Chronic administration of NT69L reduces alcohol preference and consumption in mice through modulation of the NTS1 [18]. Biochemically, NT69L normalizes the nicotine-induced changes in DA [19], the neurotransmitter that promotes the motivational process for both nicotine and alcohol, and the alcohol-induced increase in DA and glutamate in the striatum [20]. Additionally, NT modulates other neurotransmitters implicated in alcohol use disorder (AUD). It causes neurochemical changes similar to acamprosate (the calcium salt of acetylhomotaurine), which is one of three FDA-approved drugs to treat AUD. Administration of acamprosate or NT69L increases extracellular concentration of DA in striatum [10,11] and both acamprosate and NT69L modulate glutamate [21,22].Considering the behav...

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“…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]. …”

Section: Neurotensin and Substance Abusementioning

confidence: 99%

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

Boules

Fredrickson

Muehlmann

et al. 2014

Behavioral Sciences

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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.

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Neurotensin receptor type 1 regulates ethanol intoxication and consumption in mice

Cited by 37 publications

References 39 publications

Activation of neurotensin receptor type 1 attenuates locomotor activity

Activation of neurotensin receptor type 1 attenuates locomotor activity

Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats

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

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