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Journal ArticleDOI

Intraventricular administration of neuropeptide S has reward-like effects.

01 May 2011-European Journal of Pharmacology (NIH Public Access)-Vol. 658, Iss: 1, pp 16-21

TL;DR: The data suggest that intraventricular NPS injections have reward-like effects in that NPS weakly facilitates seeking and induces positive reinforcement, which may depend on intact dopamine and hypocretin systems.

AbstractNeuropeptide S (NPS) is an endogenous brain peptide produced by neurons located in the lower brainstem, and functional studies suggest that NPS has arousing effects. Because its receptors are found in reward-associated regions throughout the brain, we evaluated whether intraventricular NPS injections elicit reward-related effects in rats. Rats increased lever presses that led to intraventricular administration of NPS (0.34-34 pmol per infusion) in a dose dependent manner, with a cue-assisted procedure. Cue-assisted self-administration of NPS was decreased by systemic administration of the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.) or the hypocretin-1 (orexin-1) receptor antagonist SB 334867 (20 mg/kg, i.p.). In addition, intraventricular NPS injections (1000 pmol) induced conditioned place preference, whereas a lower dose (100 pmol) of NPS induced conditioned place aversion. Finally, NPS injections (100-1000 pmol) acutely facilitated locomotor activity, whereas repeated NPS injections did not lead to locomotor sensitization. Our data suggest that intraventricular NPS injections have reward-like effects in that NPS weakly facilitates seeking and induces positive reinforcement. These effects may depend on intact dopamine and hypocretin systems.

Topics: Neuropeptide S (59%), SCH-23390 (52%), Conditioned place preference (52%)

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Journal ArticleDOI
Abstract: Mice are increasingly overtaking the rat model organism in important aspects of anxiety research, including drug development. However, translating the results obtained in mouse studies into information that can be applied in clinics remains challenging. One reason may be that most of the studies so far have used animals displaying 'normal' anxiety rather than 'psychopathological' animal models with abnormal (elevated) anxiety, which more closely reflect core features and sensitivities to therapeutic interventions of human anxiety disorders, and which would, thus, narrow the translational gap. Here, we discuss manipulations aimed at persistently enhancing anxiety-related behavior in the laboratory mouse using phenotypic selection, genetic techniques and/or environmental manipulations. It is hoped that such models with enhanced construct validity will provide improved ways of studying the neurobiology and treatment of pathological anxiety. Examples of findings from mouse models of enhanced anxiety-related behavior will be discussed, as well as their relation to findings in anxiety disorder patients regarding neuroanatomy, neurobiology, genetic involvement and epigenetic modifications. Finally, we highlight novel targets for potential anxiolytic pharmacotherapeutics that have been established with the help of research involving mice. Since the use of psychopathological mouse models is only just beginning to increase, it is still unclear as to the extent to which such approaches will enhance the success rate of drug development in translating identified therapeutic targets into clinical trials and, thus, helping to introduce the next anxiolytic class of drugs.

74 citations


Cites background from "Intraventricular administration of ..."

  • ...In addition to its strong influence on stress-induced anxiety-related behavior, the NPS and its NPSR have been shown to be involved in many other physiological and pathological processes including depression-like behavior [306], drug seeking [312], food intake [313], respiratory function [314], asthma/atopy [315-318] and inflammatory bowel disease [319]....

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Journal ArticleDOI
TL;DR: The results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans.
Abstract: Experiments in rodents revealed neuropeptide S (NPS) to constitute a potential novel treatment option for anxiety diseases such as panic and post-traumatic stress disorder. However, both its cerebral target sites and the molecular underpinnings of NPS-mediated effects still remain elusive. By administration of fluorophore-conjugated NPS, we pinpointed NPS target neurons in distinct regions throughout the entire brain. We demonstrated their functional relevance in the hippocampus. In the CA1 region, NPS modulates synaptic transmission and plasticity. NPS is taken up into NPS receptor-expressing neurons by internalization of the receptor–ligand complex as we confirmed by subsequent cell culture studies. Furthermore, we tracked internalization of intranasally applied NPS at the single-neuron level and additionally demonstrate that it is delivered into the mouse brain without losing its anxiolytic properties. Finally, we show that NPS differentially modulates the expression of proteins of the glutamatergic system involved inter alia in synaptic plasticity. These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans.

70 citations


Cites background from "Intraventricular administration of ..."

  • ...NPS is an excellent candidate for this purpose, as, although reward-like effects have been reported by others (Cao et al, 2011), NPS does not act as a GABAA receptor agonist....

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Journal ArticleDOI
TL;DR: It is suggested that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure.
Abstract: SB-334867 has been an important ligand for the study of the orexin 1 (OX1) receptor due to its high OX1/OX2 selectivity and bioavailability. This ligand however, contains a 2-methylbenzoxazole ring system which is known to undergo hydrolysis, particularly under acidic or basic conditions. The possibility that SB-334867 would be susceptible to significant hydrolysis was evaluated in various formulations and in the solid state. SB-334867 was found to be unstable under conditions commonly employed to prepare stock solutions for in vitro and in vivo studies. In addition, and most alarmingly, the hydrochloride salt of SB-334867 was found to quantitatively decompose to an OX1-inactive product even in the solid state. These findings combine to suggest that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure.

56 citations


Journal ArticleDOI
TL;DR: The potential of the NPS system as a treatment target for addiction is analyzed, with particular attention to the interpretation of findings revealing complex neuroanatomical and functional interactions between NPS, CRF, and the Hcrt-1/Ox-A systems.
Abstract: Recent behavioral, pharmacological and molecular findings have linked the NPS system to drug dependence. Most of the evidence supports the possibility that increased NPS activity may contribute to shaping vulnerability to addiction, especially relapse. However, data suggesting that the anxiolytic-like properties of NPS may have protective effects on addiction have been also published. In addition, evidence from conditioned place preference experiments, though not unequivocal, suggests that NPS per se is devoid of motivational properties. Intriguingly, several effects of NPS on drugs of abuse appear to be mediated by downstream activation of brain corticotrophin releasing factor (CRF) and hypocretin-1/orexin-A (Hcrt-1/Ox-A) systems. The major objective of the present article is to review the existing work on NPS and addiction. Particular attention is devoted to the interpretation of findings revealing complex neuroanatomical and functional interactions between NPS, CRF, and the Hcrt-1/Ox-A systems. Original data aimed at shedding light on the role of NPS in reward processing are also shown. Finally, existing findings are discussed within the framework of addiction theories, and the potential of the NPS system as a treatment target for addiction is analyzed.

28 citations


Journal ArticleDOI
TL;DR: In the general population, the NPSR1 Asn107Ile polymorphism is associated with AUD and alcohol consumption, dependent on sex, environment and age, in line with the impulsivity and personality regulating role of the N PSR1.
Abstract: The functional polymorphism Asn(107) Ile (rs324981, A > T) of the neuropeptide S receptor (NPSR1) gene is involved in the modulation of traits that affect alcohol use. Hence, we have examined whether the NPSR1 A/T polymorphism is associated with alcohol use disorders (AUD) and alcohol use in a population-representative sample. Lifetime AUD were assessed by the MINI psychiatric interview (n = 501) in the older cohort of the longitudinal Estonian Children Personality Behaviour and Health Study at age 25. Alcohol use, environmental adversities and personality were reported by both the younger (original n = 583) and the older cohort (original n = 593) in three study waves. NPSR1 associations with AUD and alcohol use differed by sex. In females, both AUD [odds ratio (OR) = 7.20 (0.94-55.0), P = 0.029] and harmful alcohol use were more prevalent in A-allele carriers. In contrast, in males, AUD was more frequent in T-allele carriers [OR = 2.75 (1.19-6.36), P = 0.017], especially if exposed to adverse environments at age 15 [OR = 10 (1.18-84.51), P = 0.019]. Alcohol use was higher in male T-allele carriers at ages 15 and 18 as well. Similarly to females, however, the risk allele for higher alcohol use for males at age 25 was the A-allele. Many of the effects on alcohol use were explained by genotype effects on measures of personality. In the general population, the NPSR1 Asn(107) Ile polymorphism is associated with AUD and alcohol consumption, dependent on sex, environment and age. The results are in line with the impulsivity and personality regulating role of the NPSR1.

24 citations


References
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Journal ArticleDOI
TL;DR: It is found that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation, and changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.
Abstract: Progress has been made over the last 10 years in determining the neural mechanisms of sensitization induced by amphetamine-like psychostimulants, opioids and stressors. Changes in dopamine transmission in axon terminal fields such as the nucleus accumbens appear to underlie the expression of sensitization, but the actions of drugs and stressors in the somatodendritic regions of the A10/A9 dopamine neurons seem critical for the initiation of sensitization. Manipulations that increase somatodendritic dopamine release and permit the stimulation of D1 dopamine receptors in this region induce changes in the dopamine system that lead to the development of long-term sensitization. However, it is not known exactly how the changes in the A10/A9 region are encoded to permit augmented dopamine transmission in the terminal field. One possibility is that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation. Alternatively, changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.

2,017 citations


"Intraventricular administration of ..." refers background in this paper

  • ..., 2005), while behavioral sensitization depends on their actions in the ventral tegmental area (Kalivas and Stewart, 1991; Kalivas and Weber, 1988; Vezina and Stewart, 1990)....

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Journal ArticleDOI
TL;DR: Experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the vents of the ventral striatum.
Abstract: Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.

1,287 citations


"Intraventricular administration of ..." refers background in this paper

  • ...Because dopamine transmission occurring in the medial part of the ventral striatum plays a critical role in reward seeking (Ikemoto, 2007; Shin et al., 2010), the medial ventral striatum may play a critical role in cue-assisted self-administration of NPS....

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Journal ArticleDOI
19 Aug 2004-Neuron
TL;DR: It is reported that a neuropeptide, NPS, potently modulates wakefulness and could also regulate anxiety, and it is shown that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.
Abstract: Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.

446 citations


"Intraventricular administration of ..." refers background in this paper

  • ...In addition, the fact that intraventricular NPS promotes locomotor activity and wakefulness (Xu et al., 2004) makes it unclear whether increased lever pressing was due to enhanced seeking or “general” arousal....

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  • ...Neuropeptide S (NPS) is a recently identified endogenous ligand of an orphan G protein coupled receptor (Xu et al., 2004)....

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Journal ArticleDOI
TL;DR: Over a short period in the late 1990s, three groups converged on the discovery of a neuropeptide system, centred in the dorsolateral hypothalamus, that regulates arousal states, influences feeding and is implicated in the sleep disorder narcolepsy.
Abstract: Over a short period in the late 1990s, three groups converged on the discovery of a neuropeptide system, centred in the dorsolateral hypothalamus, that regulates arousal states, influences feeding and is implicated in the sleep disorder narcolepsy. Subsequent studies have illuminated many aspects of the circuitry of the hypocretin (also called orexin) system, which also influences hormone secretion and autonomic homeostasis, and have led to the hypothesis that most human narcolepsies result from an autoimmune attack against the hypocretin-producing neurons. The biochemical, physiological and anatomical components that regulate the switch between waking and sleeping are becoming clear. The rapidity with which the hypocretin story has emerged is a testament to both the conceptual and the technical evolution of genomic science in the past two decades.

415 citations


Journal Article
TL;DR: It was found that daily amphetamine injection into the A10 or A9 dopamine region, but not into the dopamine terminal fields, significantly potentiated the motor stimulant effect of peripherally administered amphetamine.
Abstract: The daily administration of indirect dopamine agonists, including amphetamine and cocaine, results in a progressive increase in the behavioral stimulant effect of these drugs. Behavioral augmentation also has been shown with opioids such as morphine, and it is known that a stimulant action on dopaminergic perikarya in the ventromedial mesencephalon is critical to the development of behavioral sensitization to morphine. To determine if amphetamine-induced behavioral sensitization might also involve the mesencephalic dopamine neurons, amphetamine was microinjected daily for 2 days into regions of the rat brain containing dopamine cell bodies (A10 and A9 dopamine regions), or dopamine terminals (nucleus accumbens and striatum), and 6 days later amphetamine was given peripherally. It was found that daily amphetamine injection into the A10 or A9 dopamine region, but not into the dopamine terminal fields, significantly potentiated the motor stimulant effect of peripherally administered amphetamine. The behavioral sensitization produced by intracranial injection of amphetamine was found to be dose-dependent. Intra-A10 injection of amphetamine also was found to potentiate the motor stimulant effect of peripheral cocaine. These data indicate that an action by amphetamine in the A10 and A9 dopamine regions may play a critical role in the development of behavioral sensitization.

339 citations


"Intraventricular administration of ..." refers background in this paper

  • ..., 2005), while behavioral sensitization depends on their actions in the ventral tegmental area (Kalivas and Stewart, 1991; Kalivas and Weber, 1988; Vezina and Stewart, 1990)....

    [...]


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