Role of the ecto-nucleotidases in the cooperative effect of adenosine and neuropeptide-S on locomotor activity in mice

Abstract

Activation of adenosine receptors modifies the action of classic neurotransmitters (i.e. dopamine, glutamate and acetylcholine) and other neuromodulators, like vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide S (NPS). Similarly to adenosine, NPS is involved in the regulation of stimulus and response to fear and arousal. Thus, the present study investigates the effects of NPS on locomotor activity in mice treated with or without α,β-methylene adenosine 5'-diphosphate (AOPCP), the inhibitor of ecto-5'-nucleotidase. Additionally, we evaluate the activity of ecto-5'-nucleotidase in brain slices of mice treated with or without NPS. Male adult CF-1 mice received i.c.v. NPS as 0.1 nmol injection with or without pre-treatment with 1 nmol α,β-methylene adenosine 5'-diphosphate (AOPCP), the selective inhibitor of ecto-5'-nucleotidase, to evaluate locomotor activity. In another set of experiments, mice received i.c.v. infusion of 0.1 nmol NPS to assay enzymatic activity in brain slices. The results demonstrated that the pre-treatment with AOPCP, which was inactive per se, prevented NPS-induced hyperlocomotion in mice. The dose of 0.1 nmol NPS was efficient to induce hyperlocomotion in animals during the observation period in the activity cage. Regarding enzymatic activity, i.c.v. NPS injection did not induce any significant alterations in ATP and AMP hydrolysis in striatum and hippocampus brain slices of mice. The present study shows that the hyperlocomotor effect of NPS depends on the ecto-5'-nucleotidase activity.

Identification of the first biased NPS receptor agonist that retains anxiolytic and memory promoting effects with reduced levels of locomotor stimulation

“…This may fit with findings by Dr. Boeck‘s group which demonstrated that the inhibition of either the adenosine(2A)-receptor or ecto-nucleotidases also block NPS-mediated hyperlocomotion. (Boeck et al, 2010; Pacheco et al, 2011) In these studies it was proposed that extracellular adenosine is permissive in the effects of NPS. Alternatively, it could be that NPS-mediates both intracellular and subsequently extracellular increases in cAMP, which would result in adenosine(2A)-receptor activation.…”

Identification of a Role for the Ventral Hippocampus in Neuropeptide S-Elicited Anxiolysis

“…Interestingly, intra-vCA1-injected NPS did not significantly alter locomotion in any of the three behavioral tests employed (Figure 3B–D), while, in contrast, former studies reported ICV-injected NPS to induce hyperlocomotion [47], [48]. This discrepancy can be explained by the fact that local application targets only one specific brain structure, whereas ICV injections will influence several brain regions.…”

Modification of caffeine effects on the affect-modulated startle by neuropeptide S receptor gene variation

“…Animal models have shown that NPS or neuropeptide S receptor agonists -corresponding to the more active NPSR T allele in humans -elicit a robustly increased arousal. As caffeine and A2A antagonists have been reported to prevent hyperarousal evoked by NPS (Boeck et al 2010;Pacheco et al 2011) potentially by decreasing brainstem NPS expression (Lage et al, 2006), startle magnitudes in response to higharousing pictures (unpleasant, pleasant) might be blunted particularly in high NPS tonus NPSR TT genotype carriers. The observed relative increase in startle response in the neutral picture condition -representing minimal emotional arousal -in carriers of the NPSR TT genotype after caffeine administration might therefore not be due to an arousal effect but rather a consequence of a general maladaptive emotional processing in NPSR TT genotype carriers (Dannlowski et al, 2011;Domschke et al, 2011).…”

“…On a behavioral level, treatment with caffeine and A2A antagonists has been reported to prevent the increase in locomotion evoked by NPS (Boeck et al 2010). Also, adenosine depletion by inhibition of ecto-nucleotidases blocked the hyperlocomotor effects of NPS (Pacheco et al 2011). In turn, NPS injections have been observed to reduce cumulative burying behavior, which is increased by caffeine (Vitale et al 2008), while a NPSR receptor antagonist did not affect the hyperlocomotor effect of caffeine in mice (Ruzza et al 2010).…”