Figure
Effect of acute restraint stress (60 min) versus homecage control on ppN/OFQ mRNA expression in the rat (a) hypothalamus, (b) basal forebrain and (c) medio-dorsal forebrain and (d) hippocampus 2 h post-restraint. Data are expressed as ppN/OFQ : GAPDH ratios (mean ± SEM, n = 6). *P < 0.05 versus respective control (Mann–Whitney U-test). The top panel shows a representative image of amplified ppN/OFQ cDNA from hippocampal mRNA in a control versus restraint-stressed animal 2 h following stress onset.
Source publication
Central nociceptin/orphanin FQ (N/OFQ)- expressing neurones are abundantly expressed in the hypothalamus and limbic system and are implicated in the regulation of activity of hypothalamo-pituitary-adrenal axis (HPA) activity and stress responses. We investigated the role of the endogenous N/OFQ receptor (NOP) system using the non-peptidic NOP antag...
Contexts in source publication
Context 1
... represent the mean ± SEM plasma corticosterone concentration (ng/ml) (n = 5/6 per group); *P < 0.05, # P < 0.05 versus vehi- cle homecage group, two-way ANOVA with post-hoc Fisher's protected least significant difference test. from the rat. Differences in hippocampal ppN/OFQ mRNA were apparent between treatment groups at 2 h post-stress onset (Fig. 3). Analysis revealed a significant difference in ppN/ OFQ : GAPDH ratios in the hippocampus (1.04 versus 0.87 between control and restraint groups, respectively; Mann-Whitney U = 3.000, P = 0.028; Fig. 3D) representing a 22% decrease in ppN/ OFQ mRNA in this region. However, the apparent trends towards a decreases in ppN/OFQ mRNA in the ...Context 2
... difference test. from the rat. Differences in hippocampal ppN/OFQ mRNA were apparent between treatment groups at 2 h post-stress onset (Fig. 3). Analysis revealed a significant difference in ppN/ OFQ : GAPDH ratios in the hippocampus (1.04 versus 0.87 between control and restraint groups, respectively; Mann-Whitney U = 3.000, P = 0.028; Fig. 3D) representing a 22% decrease in ppN/ OFQ mRNA in this region. However, the apparent trends towards a decreases in ppN/OFQ mRNA in the hypothalamus (Mann-Whitney U = 9.000, P = 0.283; Fig. 3A) and basal forebrain (Mann-Whitney U = 8.000, P = 0.214; Fig. 3B) did not reach statistical significance. Levels of ppN/OFQ mRNA in the ...Context 3
... in ppN/ OFQ : GAPDH ratios in the hippocampus (1.04 versus 0.87 between control and restraint groups, respectively; Mann-Whitney U = 3.000, P = 0.028; Fig. 3D) representing a 22% decrease in ppN/ OFQ mRNA in this region. However, the apparent trends towards a decreases in ppN/OFQ mRNA in the hypothalamus (Mann-Whitney U = 9.000, P = 0.283; Fig. 3A) and basal forebrain (Mann-Whitney U = 8.000, P = 0.214; Fig. 3B) did not reach statistical significance. Levels of ppN/OFQ mRNA in the medio-dorsal forebrain in rats subjected to restraint stress were equivalent to controls (Mann- Whitney U = 16.000, P = 1.000; Fig. 3C) (n = 6 per group). In addition to ppN/OFQ mRNA, NOP receptor mRNA ...Context 4
... 0.87 between control and restraint groups, respectively; Mann-Whitney U = 3.000, P = 0.028; Fig. 3D) representing a 22% decrease in ppN/ OFQ mRNA in this region. However, the apparent trends towards a decreases in ppN/OFQ mRNA in the hypothalamus (Mann-Whitney U = 9.000, P = 0.283; Fig. 3A) and basal forebrain (Mann-Whitney U = 8.000, P = 0.214; Fig. 3B) did not reach statistical significance. Levels of ppN/OFQ mRNA in the medio-dorsal forebrain in rats subjected to restraint stress were equivalent to controls (Mann- Whitney U = 16.000, P = 1.000; Fig. 3C) (n = 6 per group). In addition to ppN/OFQ mRNA, NOP receptor mRNA levels in the same samples were also assessed. There was a ...Context 5
... in ppN/OFQ mRNA in the hypothalamus (Mann-Whitney U = 9.000, P = 0.283; Fig. 3A) and basal forebrain (Mann-Whitney U = 8.000, P = 0.214; Fig. 3B) did not reach statistical significance. Levels of ppN/OFQ mRNA in the medio-dorsal forebrain in rats subjected to restraint stress were equivalent to controls (Mann- Whitney U = 16.000, P = 1.000; Fig. 3C) (n = 6 per group). In addition to ppN/OFQ mRNA, NOP receptor mRNA levels in the same samples were also assessed. There was a decrease in NOP : GAPDH ratios between stressed animals and controls in the hypothalamus (0.84 versus 0.57, Mann-Whitney U = 3.00, P = 0.028; Fig. 4A) reflecting a 32% decrease in mRNA in this region. At 2 h ...Similar publications
The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. A large body of evidence shows that Nociceptin/Orphanin FQ (N/OFQ) regulates ethanol intake and anxiety-like behavior. In the rat, ethanol significantly augments CeA GABA release, whereas N/OFQ diminish...
Citations
... Importantly, in the same study, the authors showed that restraint stress increased parvocellular CRF and arginine vasopressin-mRNA transcript levels 4h after stress onset, and this effect was prevented by UFP-101 (Leggett et al. 2007). Other studies showed that NOP antagonists can reduce stress-induced elevations in circulating ACTH and corticosterone, after chronic stressful situations (Vitale et al. 2009(Vitale et al. , 2017, without affecting basal corticosterone levels in naïve or acutely stressed rodents (Delaney et al. 2012;Leggett et al. 2006;Vitale et al. 2009). These findings reinforce the view that endogenous N/OFQ signaling became important in modulating HPA axis activity during prolonged stressful situations. ...
Rationale
Recently, we demonstrated that the activation of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) signaling facilitates depressive-like behaviors. Additionally, literature findings support the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal (HPA) axis.
Objectives
Considering that dysfunctional HPA axis is strictly related to stress-induced psychopathologies, we aimed to study the role of the HPA axis in the pro-depressant effects of NOP agonists.
Methods
Mice were treated prior to stress with the NOP agonist Ro 65-6570, and immobility time in the forced swimming task and corticosterone levels were measured. Additionally, the role of endogenous glucocorticoids and CRF was investigated using the glucocorticoid receptor antagonist mifepristone and the CRF1 antagonist antalarmin in the mediation of the effects of Ro 65-6570.
Results
The NOP agonist in a dose-dependent manner further increased the immobility of mice in the second swimming session compared to vehicle. By contrast, under the same conditions, the administration of the NOP antagonist SB-612111 before stress reduced immobility, while the antidepressant nortriptyline was inactive. Concerning in-serum corticosterone in mice treated with vehicle, nortriptyline, or SB-612111, a significant decrease was observed after re-exposition to stress, but no differences were detected in Ro 65-6570-treated mice. Administration of mifepristone or antalarmin blocked the Ro 65-6570-induced increase in the immobility time in the second swimming session.
Conclusions
Present findings suggest that NOP agonists increase vulnerability to depression by hyperactivating the HPA axis and then increasing stress circulating hormones and CRF1 receptor signaling.
... This is consistent with the increased expression of N/ OFQ in the hippocampus observed in the present work, but also in a previous study that used a chronic social crowding model [45]. Beside memory modulation, endogenous N/OFQ is believed to contribute to the adaptive response to acute stress, notably because of its anxiolytic properties [29,52]. Our data suggest that it could also be important for the adaptation to novel situations, by improving the encoding of relevant memories. ...
Chronic stress causes cognitive deficits, such as impairments in episodic-like hippocampus-dependent memory. Stress regulates an opioid-related neuropeptide named Nociceptin/Orphanin FQ (N/OFQ), the ligand of the G protein-coupled receptor NOP. Since this peptide has deleterious effects on memory, we hypothesized that the N/OFQ system could be a mediator of the negative effects of stress on memory. Chronic stress was mimicked by chronic exposure to corticosterone (CORT). The NOP receptor was either acutely blocked using selective antagonists, or knocked-down specifically in the hippocampus using genetic tools. Long-term memory was assessed in the object recognition (OR) and object location (OL) paradigms. Acute injection of NOP antagonists before learning had a negative impact on memory in naive mice whereas it restored memory performances in the chronic stress model. This rescue was associated with a normalization of neuronal cell activity in the CA3 part of the hippocampus. Chronic CORT induced an upregulation of the N/OFQ precursor in the hippocampus. Knock-down of the NOP receptor in the CA3/Dentate Gyrus region prevented memory deficits in the CORT model. These data demonstrate that blocking the N/OFQ system can be beneficial for long-term memory in a neuroendocrine model of chronic stress. We therefore suggest that NOP antagonists could be useful for the treatment of memory deficits in stress-related disorders.
... Classical ERs are known to regulate urocortin transcription (Haeger et al., 2006) and, therefore, the expression of classical ERs in urocortin cells of the PVN (Haeger et al., 2006) may also contribute to the regulation of the stress response. Furthermore, classical ERs in other parvocellular neuronal populations of the PVN, such as the nociceptin/orphanin FQ neurons, which express ERβ (Isgor et al., 2003b), may also potentially be involved in the stress response (Delaney et al., 2012). ...
Estradiol and hypothalamic paraventricular nucleus (PVN) help coordinate reproduction with body physiology, growth and metabolism. PVN integrates hormonal and neural signals originating in the periphery, generating an output mediated both by its long-distance neuronal projections, and by a variety of neurohormones produced by its magnocellular and parvocellular neurosecretory cells. Here we review the cyto-and chemo-architecture, the connectivity and function of PVN and the sex-specific regulation exerted by estradiol on PVN neurons and on the expression of neurotransmitters, neuromodulators, neuropeptides and neurohormones in PVN. Classical and non-classical estrogen receptors (ERs) are expressed in neuronal afferents to PVN and in specific PVN interneurons, projecting neurons, neurosecretory neurons and glial cells that are involved in the input-output integration and coordination of neurohormonal signals. Indeed, PVN ERs are known to modulate body homeostatic processes such as autonomic functions, stress response, reproduction, and metabolic control. Finally, the functional implications of the estrogenic modulation of the PVN for body homeostasis are discussed.
... In contrast to traumatic stress, changes in the N/OFQ-NOP receptor system following acute stress are transient in nature and consistent with the normal response provoked by stress exposure. In general, acute stress (restraint, single housing) increases N/OFQ peptide levels in HIPPO (CA1, CA3, and dentate gyrus (DG)), mPFC, NAc, and AMY, and reduces N/OFQ mRNA levels in those same regions 2-4 hr poststress (Delaney et al., 2012;Granholm, Roman, & Nylander, 2015 to that is the basal forebrain where exposure to acute restraint stress decreased N/OFQ immediately (Devine, Hoversten, Ueda, & Akil, 2003), while N/OFQ mRNA levels were unchanged 2-4 hours after stress (Delaney et al., 2012). Again, these regional-and time-dependent effects underscore the dynamic nature of this modulatory N/OFQ-NOP receptor system, and the importance of timing when treating with a drug that will interfere with this process. ...
... In contrast to traumatic stress, changes in the N/OFQ-NOP receptor system following acute stress are transient in nature and consistent with the normal response provoked by stress exposure. In general, acute stress (restraint, single housing) increases N/OFQ peptide levels in HIPPO (CA1, CA3, and dentate gyrus (DG)), mPFC, NAc, and AMY, and reduces N/OFQ mRNA levels in those same regions 2-4 hr poststress (Delaney et al., 2012;Granholm, Roman, & Nylander, 2015 to that is the basal forebrain where exposure to acute restraint stress decreased N/OFQ immediately (Devine, Hoversten, Ueda, & Akil, 2003), while N/OFQ mRNA levels were unchanged 2-4 hours after stress (Delaney et al., 2012). Again, these regional-and time-dependent effects underscore the dynamic nature of this modulatory N/OFQ-NOP receptor system, and the importance of timing when treating with a drug that will interfere with this process. ...
... NOP receptor mRNA increased in the central AMY (CeA) and basolateral AMY in male rats exposed to restraint stress (Ciccocioppo et al., 2014) and in CeA, basomedial amygdala and PVN 3 hours after acute social defeat stress (Green & Devine, 2009). NOP receptor mRNA decreased in the whole HYP (Delaney et al., 2012) and mediodorsal forebrain and HIPPO, 2 and 4 hours after restraint stress, respectively, but remained unchanged in basal forebrain tissue at those time points (Delaney et al., 2012). ...
The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is a member of the opioid receptor superfamily with N/OFQ as its endogenous agonist. Wide expression of the NOP receptor and N/OFQ, both centrally and peripherally, and their ability to modulate several biological functions has led to development of NOP receptor modulators by pharmaceutical companies as therapeutics, based upon their efficacy in preclinical models of pain, anxiety, depression, Parkinson’s disease, and substance abuse. Both posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are debilitating conditions that significantly affect the quality of life of millions of people around the world. PTSD and TBI both arise from traumatic events, and especially for those deployed to, working and/or living in a war zone or are first responders, they may arise from the same event and are comorbid. PTSD and TBI share common symptoms, and negatively influence outcomes as comorbidities of the other. Unfortunately, a lack of effective therapies or therapeutic agents limits the limits the long term quality of life for either TBI or PTSD patients. Ours, and other groups, demonstrated that PTSD and TBI preclinical models elicit changes in the N/OFQ-NOP receptor system, and that administration of NOP receptor ligands alleviated some of the neurobiological and behavioral changes induced by brain injury and/or traumatic stress exposure. Here we review the past and most recent progress on understanding the role of the N/OFQ-NOP receptor system in PTSD and TBI neurological and behavioral sequelae. There is still more to understand about this neuropeptide system in both PTSD and TBI, but current finding warrant further examination of the potential utility of NOP modulators as therapeutics for these disorders and their co-morbidities. We advocate the development of standards for common data elements (CDE) reporting for preclinical PTSD studies, similar to current preclinical TBI CDEs. That would provide for more standardized data collection and reporting to improve reproducibility, interpretation and data sharing across studies.
... On the other hand, administration of NOP antagonists did not change glucocorticoid and ACTH plasma levels or CRF and POMC expression levels in naïve rats (Leggett et al., 2006;Vitale et al., 2009;Zhang et al., 2015). However, the blockade of the NOP receptor exerted by specific antagonists restored circulating corticosterone plasma levels to baseline in stressed rodents (Leggett et al., 2009;Vitale et al., 2009Vitale et al., , 2017Delaney et al., 2012;Zhang et al., 2015). It is plausible to assume that stress, via glucocorticoids, increases the N/OFQ (Devine et al., 2003;Nativio et al., 2012) and NOP receptor expression (Green et al., 2009;Ciccocioppo et al., 2014) in rodents, leading to an enhancement of the endogenous N/OFQ system. ...
The role of stress in the etiology of depression has been largely reported. In this line, exogenous glucocorticoids are employed to mimic the influence of stress on the development of depression. The N/OFQ-NOP receptor system has been implicated in the modulation of stress and emotional behaviors. In fact, the blockade of NOP receptors induces antidepressant effects and increases resilience to acute stress. This study investigated the effects of the NOP receptor blockade on dexamethasone-treated mice exposed to acute and prolonged swimming stress. Swiss and NOP(+/+) and NOP(−/−) mice were treated with dexamethasone, and the protective effects of the NOP antagonist SB-612111 (10 mg/kg, ip) or imipramine (20 mg/kg, ip) were investigated in three swimming sessions. The re-exposure to swim stress increased immobility time in Swiss and NOP(+/+), but not in NOP(−/−) mice. Acute and repeated dexamethasone administration induced a further increase in the immobility time, and facilitated body weight loss in Swiss mice. Single administration of SB-612111, but not imipramine, prevented swimming stress- and dexamethasone-induced increase in the immobility time. Repeated administrations of SB-612111 prevented the deleterious effects of 5 days of dexamethasone treatment. Imipramine also partially prevented the effects of repeated glucocorticoid administration on the immobility time, but did not affect the body weight loss. NOP(−/−) mice were more resistant than NOP(+/+) mice to inescapable swimming stress, but not dexamethasone-induced increase in the immobility time and body weight loss. In conclusion, the blockade of the NOP receptor facilitates an active stress copying response and attenuates body weight loss due to repeated stress.
... The nociceptin receptor system interacts with the stress-related corticotropin-releasing factor (CRF) receptor system, as high expression of both receptors are found in regions implicated in the stress response such as the central amygdala and bed nucleus of the stria terminalis (BNST) where N/OFQ acts as a putative CRF antagonist (Ciccocioppo et al. 2014). Differences in mRNA expression levels of the precursor peptide (ppN/OFQ) in the central amygdala and BNST following acute or repeated restraint stress in rats have been observed, suggesting stress-mediated alterations in underlying mechanisms regulating the NOP receptor system (Delaney et al. 2012). In the same study, researchers found increased activity of the hypothalamicpituitary-adrenal axis following administration of the NOP antagonist JTC-801 to home-cage control rats. ...
RationaleEvaluation of pharmacotherapies for acute stress disorder (ASD) or post-traumatic stress disorder (PTSD) is challenging due to robust heterogeneity of trauma histories and limited efficacy of any single candidate to reduce all stress-induced effects. Pursuing novel mechanisms, such as the nociceptin/orphanin FQ (NOP) system, may be a viable path for therapeutic development and of interest as it is involved in regulation of relevant behaviors and recently implicated in PTSD and ASD.Objectives
First, we evaluated NOP receptor antagonism on general behavioral performance and again following a three-species predator exposure model (Experiment 1). Then, we evaluated effects of NOP antagonism on fear memory expression (Experiment 2).Methods
Adult, male rats underwent daily administration of NOP antagonists (J-113397 or SB-612,111; 0–20 mg/kg, i.p.) and testing in acoustic startle, elevated plus maze, tail-flick, and open field tests. Effects of acute NOP antagonism on behavioral performance following predator exposure were then assessed. Separately, rats underwent fear conditioning and were later administered SB-612,111 (0–3 mg/kg, i.p.) prior to fear memory expression tests.ResultsJ-113397 and SB-612,111 did not significantly alter most general behavioral performance measures alone, suggesting minimal off-target behavioral effects of NOP antagonism. J-113397 and SB-612,111 restored performance in measures of exploratory behavior (basic movements on the elevated plus maze and total distance in the open field) following predator exposure. Additionally, SB-612,111 significantly reduced freezing behavior relative to control groups across repeated fear memory expression tests, suggesting NOP antagonism may be useful in dampening fear responses. Other measures of general behavioral performance were not significantly altered following predator exposure.ConclusionsNOP antagonists may be useful as pharmacotherapeutics for dampening fear responses to trauma reminders, and the present results provide supporting evidence for the implication of the NOP system in the neuropathophysiology of dysregulations in fear learning and memory processes observed in trauma- and stress-related disorders.
... Similar increase of prepro-N/OFQ mRNA expression in the hypothalamus is observed 2 h after systemic injection of Staphylococcal enterotoxin A (SEA) to mice [96]. However, acute processive stress such as restraint stress for 120 min in rats exerts no effect on N/OFQ immunoreactivity in the hypothalamus shortly after stress [97], consistent with a finding that acute restraint for 60 min fails to alter prepro-N/OFQ and NOP receptor mRNA expression in the hypothalamus 3 h later [98]. In contrast to acute restraint stress, acute social defeat stress for 10 min in rats with or without preexposure to repeated social defeat for 5 days also increases NOP receptor mRNA expression, but not prepro-N/OFQ, in the hypothalamic paraventricular nucleus 3 h after the start of defeat [99]. ...
... In the hippocampus, acute stress changes the expression of N/ OFQ, but not NOP receptor. Acute restraint stress for 120 min in rats increases N/OFQ immunoreactivity in the CA1, CA3 and dentate gyrus of hippocampus shortly after restraint [97] while similar acute restraint stress for 60 min [98] and social defeat stress for 10 min [99] in rats fail to alter mRNA expression of prepro-N/OFQ or NOP receptor in the hippocampus 3 h after stress onset. Other lines of evidence show that acute systemic stress by injection of lipopolysaccharide in rats [95] or Staphylococcal enterotoxin A in mice [96] produces no significant change in mRNA expression of prepro-N/OFQ or NOP receptor in the hippocampus between 2 and 4 h after stress onset. ...
... Repeated social defeat for 5 days does not alter prepro-N/OFQ and NOP receptor mRNA expression in the brain 3 h after the start of social defeat [99]. In contrast, repeated restraint for 13 or 14 day significantly increases prepro-N/OFQ mRNA expression in the BNST and reticular thalamic nucleus 3 h after restraint, but there is no change in NOP receptor mRNA expression [98]. In addition, daily maternal separation for 360 min in rat litters for 3 postnatal weeks (MS360) increases N/OFQ peptide levels in the periaqueductal gray when measured 7 weeks after maternal separation procedures [106]. ...
Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K+ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.
... For Stress induction, mice were restrained in a ventilated 50ml plastic syringe (Delaney et al., 2012) and placed in an opaque surface for 90 minutes. After 90 minutes the animal was transferred to the cage for 5 minutes interval and thereafter mice were evaluated for behavior changes using elevated plus maze (EPM), open field test (OFT) and dark light box test. ...
Stress is a state that seriously disturbs psychological or physiological homeostasis of the body and subsequently affects the morphology and function of the hippocampus. Currently available anti-stress medications provide limited benefits with cost of severe adverse effects. In the present study, effect of Rosa moschata extract was evaluated using acute restraint model in mice. The stress suppressant activity of Rosa moschata was evaluated by using elevated plus maze test (EPM), dark light box test and open field test (OFT) following restraint stress protocol. Results showed that the Rosa moschata extract significantly enhanced the number of transitions and the time spent in the open arm in the EPM, increased the number of transitions and time spent in the light compartment of the dark light box, and also enhanced the locomotor activity in OFT, as compared to the stress group. In addition, LD 50 of the plant extract is greater than 5000mg/Kg. Thus the findings of our studies show that Rosa moschata significantly alleviates stress following the acute restraint stress in mice. Further studies dealing with underlying mechanism and characterization of active fraction/compound may provide an alternative therapy for stress and related neurological conditions.
... The role of the N/OFQ-NOP receptor system in modulating resilience to stress is still unclear. Of note, conflicting results have been reported about the expression of the N/OFQ and its receptor NOP in the rodent brain under stressful situations (Ciccocioppo et al., 2014;Delaney et al., 2012;Devine et al., 2003;Granholm et al., 2015;Green et al., 2009aGreen et al., , 2009bNativio et al., 2012). For example, acute restraint stress enhanced N/OFQ expression in the hippocampus (Nativio et al., 2012), while a reduction of the peptide levels was detected at the basal forebrain under similar conditions (Devine et al., 2003). ...
... Concerning the NOP receptor, an increase in NOP mRNA was detected in the amygdala and hypothalamus of rats exposed to acute stressful stimuli (Ciccocioppo et al., 2014;Green et al., 2009a). By contrast, a reduction in the receptor transcripts was observed in the same brain areas under analogous conditions (Delaney et al., 2012). These contradictory findings may be related to individual susceptibilities to stress that were neglected when interpreting these results. ...
Background:
The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear.
Aims:
The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress.
Methods:
The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated.
Results:
The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture.
Conclusions:
These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.
... This can manifest as an acute event (Devine et al., 2003;Nazzaro et al., 2010) or as a response to repeated stress (Kö ster et al., 1999). Because of their consistent anxiolytic effects, growing literature has targeted sites like the central amygdala and the bed nucleus of the stria terminalis (Ciccocioppo et al., 2003(Ciccocioppo et al., , 2014Cruz et al., 2012;Delaney et al., 2012). In each of these sites, NOPR/nociceptin appears to consistently reduce stress responses. ...
The mesocorticolimbic pathway is canonically known as the "reward pathway." Embedded within the center of this circuit is the striatum, a massive and complex network hub that synthesizes motivation, affect, learning, cognition, stress, and sensorimotor information. Although striatal subregions collectively share many anatomical and functional similarities, it has become increasingly clear that it is an extraordinarily heterogeneous region. In particular, the nucleus accumbens (NAc) medial shell has repeatedly demonstrated that the rules dictated by more dorsal aspects of the striatum do not apply or are even reversed in functional logic. These discrepancies are perhaps most easily captured when isolating the functions of various neuromodulatory peptide systems within the striatum. Endogenous peptides are thought to play a critical role in modulating striatal signals to either amplify or dampen evoked behaviors. Here we describe the anatomical-functional backdrop upon which several neuropeptides act within the NAc to modulate behavior, with a specific emphasis on nucleus accumbens medial shell and stress responsivity. Additionally, we propose that, as the field continues to dissect fast neurotransmitter systems within the NAc, we must also provide considerable contextual weight to the roles local peptides play in modulating these circuits to more comprehensively understand how this important subregion gates motivated behaviors.
