General features of Multiple System Atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of a group of neurodegenerative diseases referred to collectively as the ‘parkinsonian syndromes’. Characteristic of these syndromes is that the patient exhibits symptoms of ‘parkinsonism’, viz., a range of problems involving movement, most typically manifest in Parkinson’s disease (PD) itself1, but also seen in progressive supranuclear palsy (PSP), and to some extent in dementia with Lewy bodies (DLB). MSA is a relatively ‘new’ descriptive term and is derived from three previously described diseases, viz., olivopontocerebellar atrophy, striato-nigral degeneration, and Shy-Drager syndrome. The classical symptoms of MSA include parkinsonism, ataxia, and autonomic dysfunction.6 Ataxia describes a gross lack of coordination of muscle movements while autonomic dysfunction involves a variety of systems that regulate unconscious bodily functions such as heart rate, blood pressure, bladder function, and digestion. Although primarily a neurological disorder, patients with MSA may also develop visual signs and symptoms that could be useful in differential diagnosis. The most important visual signs may include oculomotor dysfunction and problems in pupil reactivity but are less likely to involve aspects of primary vision such as visual acuity, colour vision, and visual fields. In addition, the eye-care practitioner can contribute to the management of the visual problems of MSA and therefore, help to improve quality of life of the patient. Hence, this first article in a two-part series describes the general features of MSA including its prevalence, signs and symptoms, diagnosis, pathology, and possible causes.

The pharmacology of centrally acting drugs in animals of altered thyroid status

The pharmacological effects of a number of centrally acting drugs have been compared in euthyroid mice and mice made hyperthyroid by pretreatment with sodium-1-thyroxine. The potencies of two barbiturates, pentobarbitone and thiopentone - as indicated by the duration of their hypnotic actions and their acute toxicities - are increased in hyperthyroid mice. An acutely active uncoupler of phosphorylative oxidation is 2, 4-dinitrophenol, an agent which proved to be a potent hypnotic when administered intracerebrally. An attempt has been made to relate the mechanism of action of the barbiturates to the uncoupling effects of thyroxine and 2, 4-dinitrophenol. The pharmacological effects of chlorpromazine, reserpine and amphetamine-like drugs have also been studied in hyperthyroid mice. After pretreatment with thyroxine, mice show a reduced tendency to become hypothermic after chlorpromazine or reserpine; in fact, under suitable laboratory conditions these agents produce a hyperthermic effect. Yet their known depressant effects upon locomotor activity were not substantially altered. Thus it appeared that depression of locomotor activity and hypothermia are not necessarily correlated, an observation at variance with previously held opinion. These results have been discussed in the light of our knowledge of the role of the thyroid gland in thermoregulation. The actions of tremorine and its metabolite, oxotremorine, have also been examined. Hyperthyroid animals are less susceptible to both the hypothermia and tremor produced by these agents. An attempt is made to explain these observations, in view of the known mechanism of action of oxotremorine and the tremorgenic actions that thyroxine may have. A number of experimental methods have been used to study the anti-nociceptive (analgesic) effects of drugs in euthyroid and hyperthyroid mice. The sites and mechanisms of action of these drugs and the known actions of thyroxine have been discussed.

Visual signs and symptoms of multiple system atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of the 'parkinsonian syndromes', which also include Parkinson's disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB) and corticobasal degeneration (CBD). Multiple system atrophy is a complex syndrome, in which patients exhibit a variety of signs and symptoms, including parkinsonism, ataxia and autonomic dysfunction. It can be difficult to separate MSA from the other parkinsonian syndromes but if ocular signs and symptoms are present, they may aid differential diagnosis. Typical ocular features of MSA include blepharospasm, excessive square-wave jerks, mild to moderate hypometria of saccades, impaired vestibular-ocular reflex (VOR), nystagmus and impaired event-related evoked potentials. Less typical features include slowing of saccadic eye movements, the presence of vertical gaze palsy, visual hallucinations and an impaired electroretinogram (ERG). Aspects of primary vision such as visual acuity, colour vision or visual fields are usually unaffected. Management of the disease to deal with problems of walking, movement, daily tasks and speech problems is important in MSA. Optometrists can work in collaboration with the patient and health-care providers to identify and manage the patient's visual deficits. A more specific role for the optometrist is to correct vision to prevent falls and to monitor the anterior eye to prevent dry eye and control blepharospasm.

Quantitative pathological changes in the cerebellum of multiple system atrophy

Multiple system atrophy (MSA) is a rare neurodegenerative disorder associated with parkinsonism, ataxia, and autonomic dysfunction. Its pathology is primarily subcortical comprising vacuolation, neuronal loss, gliosis, and α-synuclein-immunoreactive glial cytoplasmic inclusions (GO). To quantify cerebellar pathology in MSA, the density and spatial pattern of the pathological changes were studied in α-synuclein-immunolabelled sections of the cerebellar hemisphere in 10 MSA and 10 control cases. In MSA, densities of Purkinje cells (PC) were decreased and vacuoles in the granule cell layer (GL) increased compared with controls. In six MSA cases, GCI were present in cerebellar white matter. In the molecular layer (ML) and GL of MSA, vacuoles were clustered, the clusters exhibiting a regular distribution parallel to the edge of the folia. Purkinje cells were randomly or regularly distributed with large gaps between surviving cells. Densities of glial cells and surviving neurons in the ML and surviving cells and vacuoles in the GL were negatively correlated consistent with gliosis and vacuolation in response to neuronal loss. Principal components analysis (PCA) suggested vacuole densities in the ML and vacuole density and cell losses in the GL were the main source of neuropathological variation among cases. The data suggest that: (1) cell losses and vacuolation of the GCL and loss of PC were the most significant pathological changes in the cases studied, (2) pathological changes were topographically distributed, and (3) cerebellar pathology could influence cerebral function in MSA via the cerebello-dentato-thalamic tract.

Blockade of interleukin-6 effects on cytokine profiles and macrophage activation after spinal cord injury in mice

The objective of this study was to clarify the effects of a temporal blockade of IL-6/IL-6 receptor (IL-6R) engagement, using an anti-mouse IL-6R monoclonal antibody (MR16-1), on macrophage activation and the inflammatory response in the acute phase after spinal cord injury (SCI) in mice. MR16-1 antibodies versus isotype control antibodies or saline alone was administered immediately after thoracic SCI in mice. MR16-1-treated group samples showed increased neuronal regeneration and locomotor recovery compared with controls. Immunoblot analysis of the MR16-1-treated samples identified downregulation of Th1 and upregulation of Th2 cytokines. MR16-1 treatment promoted arginase-1-positive, CD206-positive M2 macrophages, with preferential localization of these cells at the injury site and enhanced positivity for Mac-2 and Mac-3, suggestive of increased phagocytic behavior. The results suggest that temporal blockade of IL-6 signaling after SCI abrogates damaging inflammatory activity and promotes functional recovery by promoting the formation of alternatively activated M2 macrophages.

Physiological performance measures and tolerance limits of estuarine indicator species in south Florida

Current water management practices in South Florida have negatively impacted many species inhabiting Florida Bay. Variable and high salinity has been identified as a key stressor in these estuaries. The Comprehensive Everglades Restoration Plan (CERP) includes water redistribution projects that will restore natural freshwater flows to northeastern Florida Bay. My studies focused on the following central theme and hypotheses: Biological performance measures (i.e., growth, reproduction, survival), behavior (i.e., habitat preference and locomotor behavior) and diversity of estuarine fish will be controlled by changes in salinity and water quality that will occur as a result of the restoration of freshwater flow to the bay. A series of acute and subchronic physiological toxicity studies were conducted to determine the effects of salinity changes on the life stages (embryo/larval, juvenile, adult) and fecundity of four native estuarine fish (Cyprinodon variegatus, Floridichthys carpio, Poecilia latipinna, and Gambusia holbrooki). Fish were exposed to a range of salinity concentrations (freshwater to hypersaline) based on salinity profiles in the study areas. Growth (length, weight) and survival were measured. Salinity trials included both rapid and gradual change events. Results show negative effects of acute, abrupt salinity changes on fish survival, development and reproductive success as a result of salinity stress. Other studies targeted reproduction and critical embryo-larval/neonate development as key areas for detecting long-term population effects of salinity change in Florida Bay. Adults of C. variegates and P. latipinna were also examined for behavioral responses to pulsed salinity changes. These responses include changes in swimming performance, locomotor behavior and zone preference. Finally, an ecological risk assessment was conducted for adverse salinity conditions in northeastern Florida Bay. Using the U.S. EPA's framework, the risk to estuarine fish species diversity was assessed against regional salinity profiles from a 17-year database. Based on the risk assessment, target salinity profiles for these areas are recommended for managers.^

Physiological performance measures and tolerance limits of estuarine indicator species in South Florida

Current water management practices in South Florida have negatively impacted many species inhabiting Florida Bay. Variable and high salinity has been identified as a key stressor in these estuaries. The comprehensive Everglades Restoration Plan (CERP) includes water redistribution projects that will restore natural freshwater flows to northeastern Florida Bay. My studies focused on the following central theme and hypotheses: Biological performance measures (i.e., growth, reproduction, survival), behavior (i.e., habitat preference and locomotor behavior) and diversity of estuarine fish will be controlled by changes in salinity and water quality that will occur as a result of the restoration of freshwater flow to the bay. A series of acute and subchronic physiological toxicity studies were conducted to determine the effects of salinity changes on the life stages (embryo/larval, juvenile, adult) and fecundity of four native estuarine fish (Cyprinodon variegatus, Floridichthys carpio, Poecilia latipinna, and Gambusia holbrooki). Fishe were exposed to a range of salinity concentrations (freshwater to hypersaline) based on salinity profiles in the study areas. Growth (length, weight) and survival were measured. Salinity trials included both rapid and gradual change events. Results show negative effects of acute, abrupt salinity changes on fish survival, development and reproductive success as a result of salinity stress. Other studies targeted reproduction and critical embryo-larval/neonate development as key areas for detecting long-term population effects of salinity change in Florida Bay. Adults of C. variegatus and P. latipinna were also examined for behavioral responses to pulsed salinity changes. These responses include changes in swimming performance, locomotor behavior and zone preference. Finally, an ecological risk assessment was conducted for adverse salinity conditions in northeastern Florida Bay. Using the U.S. EPA's framework, the risk to estuarine fish species diversity was assessed against regional salinity profiles from a 17-year database. Based on the risk assessment, target salinity profiles for these areas are recommended for managers.

Circadian rhythm disruption and post-surgical recovery

Circadian rhythms, patterns of each twenty-four hour period, are found in most bodily functions. The biological cycles of between 20 and 28 hours have a profound effect on an individual's mood, level of performance, and physical well being. Loss of synchrony of these biological rhythms occurs with hospitalization, surgery and anesthesia. The purpose of this comparative, correlational study was to determine the effects of circadian rhythm disruption in post-surgical recovery. Data were collected during the pre-operative and post-operative periods in the following indices: body temperature, blood pressure, heart rate, urine cortisol level and locomotor activity. The data were analyzed by cosinor analysis for evidence of circadian rhythmicity and disruptions throughout the six day study period which encompassed two days pre-operatively, two days post-operatively, and two days after hospital discharge. The sample consisted of five men and five women who served as their own pre-surgical control. The surgical procedures were varied. Findings showed evidence of circadian disruptions in all subjects post-operatively, lending support for the hypotheses.

Efeito de ligantes do receptor NOP no modelo animal de mania induzido por metilfenidato

Bipolar disorder is a chronic psychopathology that reaches from 1 to 4% of the world population. This mood disorder is characterized by cyclical mood changes, in which an individual alternates between states of depression and mania. Mania is described in the literature as an abnormal state of exacerbation of humor, in which the subject presents an expansive, euphoric behavior, but with increased irritability, psychomotor agitation and a feeling of invincibility, which will contribute to risks exposure. The treatment of this psychopathology is complex and it is not effective in all cases, and it evokes many side effects. In this respect, the system of Nociceptin/Orphanin FQ (N/OFQ) can be studied as a possible therapeutic target for the treatment of bipolar disorder, due to its modulatory role on monoaminergic systems and on mood. This study aims to investigate the effect of NOP receptor ligands in an animal model of mania induced by methylphenidate. To this aim, locomotor activity was assessed in an open field, in mice treated with methylphenidate (10 mg/kg, sc, 15 min). Valproate (300 mg / kg, ip, 30 min), standard treatment of mania, prevented methylphenidate-induced hyperlocomotion. The acute treatment with the antagonist of NOP receptor UFP-101 (1-10 nmol, icv, 5 min) per se did not affect the spontaneous locomotion of mice, but it was able of attenuating hyperlocomotion induced by methylphenidate. The acute treatment with N/OFQ (1 and 0.1 nmol, icv, 5 min) did not alter the distance moved, but when tested at a dose of 1 ηmol, N/OFQ slightly reduced methylphenidate-induced hiperlocomotion. In conclusion, the administration of UFP-101 and N/OFQ produced antimanic-like actions. Furthermore, these data suggest that the system of N/OFQ performs a complex modulation of voluntary movement, and consequently on dopaminergic neurotransmission.

Modelo animal da Doença de Parkinson baseado na expressão de alfa - sinucleína: caracterização comportamental, eletrofisiológica e avaliação dos efei tos da estimulação da medula espinhal

Parkinson disease (PD) is associated with motor symptoms and dopaminergic cell loss in the nigrostriatal pathway. Alpha-synuclein is the major component of the Lewy bodies, the biological hallmarks of disease, and has been associated with familial cases of PD. Recently, the spinal cord stimulation (SCS) showed to be effective to alleviate the Parkinson symptoms in animal models and human patients. In this project, we characterized the motor and electrophysiological effects of alpha-synuclein overexpression in the substantia nigra of rats. We further investigated the effects of spinal electrical stimulation, AMPT and L-dopa administration in this model. Method: Sprague-Dawley rats were injected with empty viral vector or the vector carrying the gene for alpha-synuclein in the substantia nigra, and were tested weekly for 10 weeks in the open field and cylinder tests. A separated group of animals implanted with bilateral electrode arrays in the motor cortex and the striatum were recorded in the open field, during the SCS sessions and the pharmacological experiments. Results: Alpha-synuclein expression resulted in motor asymmetry, observed as the reduction in use of contralateral forepaw in the cylinder test. Animals showed an increase of local field potential activity in beta band three and four weeks after the virus injection, that was not evident after the 5th week. AMPT resulted in a sever parkinsonian state, with reduction in the locomotor activity and significant peak of oscillatory activity in cortex and striatum. SCS was effective to alleviate the motor asymmetry at long term, but did not reduce the corticostriatal low frequency oscillations observed 24 hs after the AMPT administration. These oscillations were attenuated by L-dopa that, even as SCS, was not effective to restore the locomotor activity during the severe dopaminergic depletion period. Discussion: The alpha-synuclein model reproduces the motor impairment and the progressive neurodegenerative process of PD. We demonstrated, by the first time, that this model also presents the increase in low frequency oscillatory activity in the corticostriatal circuit, compatible with parkinsonian condition; and that SCS has a therapeutic effect on motor symptom of this model.

A cafeína como agente modulador do ciclo atividade-repouso e memória em saguis (Callithrix jacchus)

Caffeine is the most consumed psychostimulant, with effects on attention, memory, and arousal. But when this substance is ingested near to bedtime there is a decrease on sleep, interfering on mnemonic processes. So, our ain was to investigate how the caffeine ingested near to sleep onset acts on sleep and memory in marmosets. We used 16 adult marmosets, single housed, in a 12:12h light-dark cycle. For registering locomotor activity were used two kinds of sensors. The gyroscope sensor registers activity each 30 sec and detects motion with good accuracy. Because of this we used this sensor for detecting nocturnal activity. The second sensor was based on infrared and accumulates activity each 5 min and it’s not able to detect nocturnal activity, just diurnal activity. We also used camera for registering Rest phase of one marmoset. For the cognitive task, the animals needed to learn a rewarded context (CR) when compared to a non-rewarded context CNR). This experiment comprises 5 phases: 1) Two days of habituation to apparatus; 2)Training for 8 days; 3) oral administration of caffeine (10 mg/kg) or placebo administration ±1h before sleep onset, for 8 days, with marmosets receiving placebo or caffeine; 4) retraining to apparatus and after that, placebo administration (placebo group-GP), or caffeine administration (with continuous group-GC and acute groupGA); 5) Test, for evaluating learning to CR. The sessions were filmed and each one had 8 min of duration. At 7 am started the habituation, training and test sessions, and at 3:15 pm started retraining. The results for gyroscope sensor showed that there was coincidence of 68,57% with nocturnal register of the cameras. Then, the gyroscope sensors detected nocturnal activity for all experimental groups Moreover, when compared sensor gyroscope with sensor based on infrared, was observed that both sensor presented similarity on patterns of activity curve. When we observed the effects of caffeine on Activity-Rest Cycle in GP, GA and GC, is possible to see that that gyroscope sensors and based on infrared presented only intra group differences. As behavioral results, the marmosets learned to discriminate CR when compared to CNR. Moreover, GP presented deficits on memory recall during the test, and GA increased the memory recall, when both were compared to GP. We concluded that the marmosets were able to learning the cognitive task and that the caffeine ingested near to sleep onset acts modulating memory in these animals. Moreover the gyroscope sensor can be used as alternative tool for investigating nocturnal activity. Then, the utilization of this non-invasive device allows marmosets exhibit their behavior within the laboratory conditions as natural as possible.

Avaliação dos efeitos da retirada do etanol em curto e longo prazo sobre respostas comportamentais relacionadas à ansiedade e sobre células imunorreativas para a serotonina no núcleo dorsal da Rafe em ratas

Ethanol withdrawn individuals present a wealth of signs and symptoms, some of them related with anxiety. To better understand brain areas involved in anxiety caused by ethanol abstinence, preclinical studies have been employing models of ethanol consumption followed by withdrawal in rodents submitted to behavioral tests of anxiety, such as the elevated plus-maze. The aim of this study was to investigate if short- or long-term ethanol withdrawal could alter both anxiety-related behaviors in the elevated plus-maze (EPM) and open field tests and the number of serotonin immunorreactive cels in the dorsal raphe nucleus, a midbrain area associated with anxiety. Female Wistar rats (90 days old) were submitted to increasing concentrations of ethanol (2% for 3 days, 4% for 3 days and 6% for 15 days) as the only source of liquid diet and the control group received water ad libitum. Both groups received food ad libitum. In the behavioral experiments, on 21st day of consumption, ethanol was substituted by water (withdrawal) and 72 h or 21 days after withdrawal animals were submitted to the EPM, where it was evaluated the percentage of time and entries in the open arms and the entries in the enclosed arms during 5 minutes. Twenty and four hours after testing in the EPM, animals were submitted to the open field test for 15 minutes, where the distance traveled by the animals was observed along this period. During the first 5 minutes, the distance traveled, entries and time spent in the center of the test were analyzed. In the immunohistochemistry study, animals were submitted to 21 days of consumption of ethanol followed or not by 72 hours and 21 days of withdrawal previously perfusion, brain tissue preparation and quantification of serotonin dyed cells in the dorsal and caudal portions in the dorsal raphe nucleus. Behavioral data showed that both short- and long-term ethanol withdrawals reduced the open arms exploration in the EPM. In the open field test there were no locomotor activity changes during the total 15 minutes; however, longterm ethanol withdrawal reduced the exploration in the center of the open field during the first 5 minutes. In the immunohistochemistry step, there were no differences, when short- and long-term withdrawn groups were compared with control group; nevertheless, the chronic consumption of ethanol decreased the number of serotonergic immunorreactive cells in the dorsal part of dorsal raphe nucleus. Taken together, results here obtained suggest that both short- and long-term ethanol withdrawals promoted an anxiogenic-like effect that was not related with changes in the serotonin immunorreactivity in the dorsal and caudal parts of the dorsal raphe nucleus.

Influência de mudanças de fase no ciclo claro-escuro sobre o controle autonômico cardíaco de ratos

Introduction: The circadian system has neural projections for the Autonomic Nervous System (ANS), directly interfering with sympathetic-vagal modulation of the cardiovascular system. Disturbances in the circadian system, such as phase changes in light-dark cycle (LD), has been related to the risk of development of cardiovascular diseases due to increased sympathetic tone and reduction o Heart Rate Variability (HRV - RR intervals). Purpose: Investigate the interaction between Circadian Timing System and cardiac autonomic control in rats. Materials and methods: We used 18 Wistar rats (♀, age = 139.9 ± 32.1 days, weight = 219.5 ± 16.2 g), divided into three distinct groups: Control (CG), phase delay of 6h (GDe) and phase advance of 6h (GAd). Three animals were excluded during data collection (CG/GDe/GAd - n=5). Telemeters were surgically implanted in each animal for continuous acquisition of electrocardiographic (ECG) signals (duration of 21 days in the CG and 28 days in GDe/ GAd). A LD cycle was established 12h: 12h, beginning of light at18:00h and dark at 06:00h. The animals remained in the same CG LD cycle throughout the experimental period, while, on the 14th day of registration, the GDe and GAd underwent a delay and an advance in 6h, respectively. Throughout the experimental period, the locomotor activity (LA), the mean heart rate (mHR) and variables related to iRR [mean RR (mRR), SDNN, RMSSD, LF, HF and LF/ HF ratio ] were recorded. All data were analyzed in blocks of 3 and 7 days, for the presence of circadian rhythm, values of Cosinor - mesor, amplitude and acrophase (paired t test), phase relationship, differences between light and dark (t test independent), averages every 30 minutes along each time series (two-way ANOVA with post hoc Bonferroni). The data block B1,M1 and M2 in CG served as benchmarks for comparisons between series of analysis of the GAT/GAV. Results: We observed circadian rhythmicity in the variables LA, mRR and mFC(p<0.01). mRR and mFC showed phase relationship with the LA in all three groups, being less stable in GAd. In the CG, no significant differences between blocks were found in any of the analyzes(p>0.05). Among the 7 day blocks, there was a significant reduction in mRR(p=0.04) and mFC(p=0.03) in GDe and significant reduction in HF mean(p=0.02) in GAd; and between 3 day blocks, a significant increase of LF/HF(p= 0.04) in the GDe; besides mRR(p=0.03), SDNN(p=0.04), RMSSD (p=0.04), LF (p=0.01) and HF(p=0.02) significant increase in the GAd. It was found that the differences between the means of the mRR, LA and mFC in light and dark phases were not significant after phase changes in some of the blocks/moments (GDe and GAd). No significant results were found when comparing rhythmic variables means every 30 minutes over the blocks, except for a significant decrease in mRR at the middle of the dark phase (B2) and the start of light phase (B3) - (p<0.01). Conclusion: phase advances and delays (6h) altered cardiac autonomic control in the experimental groups by temporarily HRV decrease. Phase advances apparently had greater negative interference in this process, in relation to the phase delays.

Organização nuclear do sistema serotonérgico no encéfalo de morcegos Artibeus planirostris

Serotonin or 5-hydroxytryptamine (5-HT) is a substance found in many tissues of the body, including the nervous system acting as a neurotransmitter. Within the neuro-axis, the location of the majority of the 5-HT neurons is superimposed with raphe nuclei of the brain stem, in the median line or its vicinity, so that neuronal 5-HT can be considered a marker of the raphe nuclei. Serotonergic neurons are projected to almost all areas of the brain. Studies show the participation of serotonin in regulating the temperature, feeding behavior, sexual behavior, biological rhythms, sleep, locomotor function, learning, among others. The anatomy of these groups has been revised in many species, including mouse, rabbit, cat and primates, but never before in a bat species from South America. This study aimed to characterize the serotonergic clusters in the brain of the bat Artibeus planirostris through immunohistochemistry for serotonin. Seven adult bat males of Artibeus planirostris species (Microchiroptera, Mammalia) were used in this study. The animals were anesthetized, transcardially perfused and their brains were removed. Coronal sections of the frozen brain of bats were obtained in sliding microtome and subjected to immunohistochemistry for 5-HT. Delimit the caudal linear (CLi), dorsal (DR), median (MnR), paramedian (PMnR), pontine (PNR), magnus (MgR), pallidus (RPA) and obscurus (ROb) raphe nucleus, in addition to the groups B9 and rostral and caudal ventrolateral (RVL/CVL). The serotonergic groups of this kind of cheiroptera present morphology and cytoarchitecture relatively similar to that described in rodents and primates, confirming the phylogenetic stability of these cell clusters.

Efeitos in vivo e in vitro de agonistas parciais do receptor NOP: implicações para o tratamento da ansiedade, depressão e mania

Introduction: This study aimed to investigate the effects of the two peptide NOP partial agonists (UFP-113 and [F/G]N/OFQ(1-13)NH2) and the non peptide NOP partial agonist (AT-090) in the mouse emotional behavior as well as in the intracellular transduction pathways following the receptor binding. Methods: Male Swiss or CD-1 mice were used in this study together with NOP(+/+) and NOP(-/-) mice. The elevated plus maze (EPM) was used to evaluate the effects of compounds on anxiety-like behaviors. Diazepam and the NOP agonists, N/OFQ and Ro 65-6570, were used as positive controls in the EPM. NOP(+/+) and NOP(-/-) mice were used to evaluate the selectivity of those compounds that induced anxiolytic-like behaviors. The forced swim test (FST) was used to evaluate the effects of compounds on depressive-like behaviors. Nortriptyline and the NOP antagonists, UFP-101 and SB-612111, were used as positive controls in the FST. The effects of N/OFQ, UFP-101, SB-612111, UFP-113, [F/G]N/OFQ(1-13)NH2, and AT-090 were assessed in the methylphenidate-induced hyperlocomotion (MIH) test; in this assay valproate was used as positive control. The G protein and β-arrestin 2 transduction pathways of NOP receptor agonists (N/OFQ and Ro 65-6570), antagonist (UFP-101), and partial agonists (UFP-113, [F/G]N/OFQ(1-13)NH2, and AT-090) were also evaluated using an innovative assay that measures a bioluminescence resonance energy transfer process. For this, cell lines permanently co-expressing the NOP receptor coupled to luciferase (energy donor), and green fluorescent protein (energy acceptor) coupled to one of the effector proteins (G protein or β-arrestin 2) were used. Results: Diazepam (1 mg/kg), N/OFQ (1 nmol), Ro 65-6570 (0.1 mg/kg), and AT-090 (0.01 mg/kg) induced anxiolytic-like effect in mice in the EPM. The effects of Ro 65-6570 and AT-090 were selective to NOP receptor. UFP-113 (0.01-1 nmol) and [F/G]N/OFQ(1-13)NH2 (0.1-3 nmol) were inactive in the EPM. In the FST, nortriptyline (30 mg/kg), UFP-101 (10 nmol), SB-612111 (10 mg/kg), UFP-113 (0.01 and 0.1 nmol), and [F/G]N/OFQ(1-13)NH2 (0.3 and 1 nmol) induced antidepressant-like effects, while AT-090 (0.001-0.1 mg/kg) was inactive in this assay. The effects of UFP-113 and [F/G]N/OFQ(1-13)NH2 were selective to NOP receptor. Valproate (400 mg/kg) counteracted methylphenidate (MPH, 10 mg/kg)-induced hyperlocomotion in mice in the open field. N/OFQ (1 nmol), UFP-113 (0.01-0.1 nmol), and [F/G]N/OFQ(1-13)NH2 (1 nmol) were also able to reduce the MPH-induced hyperlocomotion, without changing the locomotor activity per se. The effect of UFP-113 was selective to NOP receptor. The UFP-101 (10 nmol), SB-612111 (10 mg/kg), and AT-090 (0.001-0.03 mg/kg) did not change the hyperlocomotor effect of methylphenidate. In vitro, N/OFQ and Ro 65-6570 behaved as NOP full agonists for G-protein and β-arrestin 2 pathways. AT-090 behaved as NOP receptor partial agonist for both transduction pathways, while UFP-113 and [F/G]N/OFQ(1-13)NH2 behaved as partial agonists and antagonists of NOP receptor for NOP/G protein and NOP/β-arrestin 2, respectively. UFP-101 behaved as NOP receptor antagonist for both transduction pathways. Conclusion: NOP ligands producing same effects on NOP/G protein interaction (partial agonism), but with opposite effects on β-arrestin 2 recruitment (partial agonism vs antagonism), can promote different in vivo effects on anxiety and mood as it was observed in the behavioral tests. This work corroborates the potential of NOP receptor as an innovative pharmacological target for the treatment of emotional disorders.