Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S‐expressing neurons in the rat brain

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.

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Ionescu

Dine

Yen

et al. 2012

“…Brain in situ hybridization revealed that the NPS peptide is expressed principally in a group of previously undescribed neurons located between the locus ceruleus (LC), the barrington, and the parabrachial nuclei. In the area between the LC and the barrington nucleus, NPS mRNA is predominantly expressed in glutamatergic cells, whereas in the parabrachial area, its expression overlaps that of corticotrophin releasing factor positive neurones (Xu et al, 2004(Xu et al, , 2007. NPS receptor mRNA is expressed throughout the central nervous system, with the highest concentration found in olfactory structures, in the amygdaloid complex, in the subiculum, in the lateral, dorsomedial and ventromedial hypothalamus, and in the paraventricular thalamic nucleus (Xu et al, 2004(Xu et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

“…In the area between the LC and the barrington nucleus, NPS mRNA is predominantly expressed in glutamatergic cells, whereas in the parabrachial area, its expression overlaps that of corticotrophin releasing factor positive neurones (Xu et al, 2004(Xu et al, , 2007. NPS receptor mRNA is expressed throughout the central nervous system, with the highest concentration found in olfactory structures, in the amygdaloid complex, in the subiculum, in the lateral, dorsomedial and ventromedial hypothalamus, and in the paraventricular thalamic nucleus (Xu et al, 2004(Xu et al, , 2007. Activation of NPSR by intracerebroventricular (ICV) injection of NPS evokes a unique pattern of responses, including stimulation of locomotor activity, increased arousal and suppression of all stages of sleep, but also decreased experimental anxiety (Reinscheid et al, 2005;Xu et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Persistent Increase of Alcohol-Seeking Evoked by Neuropeptide S: an Effect Mediated by the Hypothalamic Hypocretin System

Cannella

Economidou

Kallupi

et al. 2009

102

The association of ethanol's reinforcing effects with specific environmental stimuli is thought to be a critical factor for relapse risk in alcoholism. This study examined in rats the effects of a newly deorphanized neuropeptide receptor and its cognate ligand, Neuropeptide S (NPS), on ethanol consumption and reinstatement of ethanol-seeking by environmental cues previously associated with ethanol availability. In the self-administration experiments, the stable response rates observed for ethanol reinforcement were not modified by intracerebroventricular (ICV) injection of NPS (1.0 and 2.0 nmol per rat). In the reinstatement experiments, ethanol-associated cues induced robust rates of ethanol seeking, which were highly resistant to extinction over repeated sessions of reinstatement testing. ICV NPS treatment (1.0, 2.0 and 4.0 nmol per rat) resulted in a significant increase of ethanol seeking elicited by ethanol-associated cues. In contrast, NPS did not affect the reinstatement of responding to water-paired stimuli. Site-specific NPS injection (0.1 and 0.5 nmol per rat) into the lateral hypothalamus also reinstated extinguished responding to ethanol. This effect was selectively blocked by pre-treatment with the hypocretin-1/orexin-A antagonist SB-334867 (10 mg/kg, i.p.). At the dose tested, SB-334867 did not modify alcohol reinstatement per se. These results provide the first demonstration that activation of NPS receptors in the LH intensifies relapse to ethanol-seeking elicited by environmental conditioning factors. This effect is selective, and is mediated by activation of LH hypocretin neurones. Based on the present findings, we also predict that antagonism at NPS receptors could represent a novel pharmacological approach to alcohol relapse treatment.

“…Anatomically, both NPS precursor and receptor mRNAs are found predominately in the central nervous system (Xu et al, 2007). Functionally, central administration of NPS increases locomotor activity in both naïve and habituated mice, effects that are abolished in mice with a disruption of the NPSR (Duangdao et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Chronic Ethanol Potentiates the Effect of Neuropeptide S in the Basolateral Amygdala and Shows Increased Anxiolytic and Anti-Depressive Effects

Enquist

Ferwerda

Madhavan

et al. 2012

Alleviating anxiety and depression is pivotal for reducing the risk of relapse in alcoholics. Currently available anxiolytic treatments are limited by side effects, including reduced efficacy in alcoholics, addiction, and sedation. We examined whether the neuropeptide S receptor (NPSR) was effective at controlling ethanol consumption and the anxiety and depression produced by forced abstinence from ethanol. We found that the anxiolytic and anti-depressant effects of NPS are enhanced in acute ethanol abstinent mice. In addition, we found that NPS reduced ethanol consumption and is not in and of itself rewarding. We also provide evidence that ethanol consumption increases the ability of NPS to modulate neuronal activity in the basolateral amygdala. Finally, we found that local injection of NPS in the basolateral amygdala promotes anxiolysis after chronic ethanol consumption, thereby providing insight into the molecular mechanism underlying the changes in behavioral response to NPS. In light of the improved anxiolytic efficacy and benign side effects of NPS in ethanol-withdrawn animals, the NPSR may prove a suitable target for reducing relapse in alcoholism.