Orexin receptor blockers: A tool for lowering alcohol intake and alcohol addictive behavior in the light of preclinical studies

Abstract Alcohol use disorder (AUD) is a severe and globally widespread neurological and psychiatric problem. The treatment with currently used drugs often does not bring the expected effect. New optimization methods or directions in pharmacotherapy are still being sought. The group of bioactive ligands, targeted at neuropeptides called orexins (OXs) and their receptors (OXRs), affects a number of functions including ingestion, sleep-wake regulation, as well as the brain reward system which is the basis of addiction. The purpose of this paper is to systematize the knowledge in the field of preclinical behavioral studies on rodents (rats and mice) in several models of alcohol consumption using the OXRs antagonists. The results of the experiments indicated a potential efficacy of particular OXRs antagonists in the AUD treatment, especially those selectively blocking the OX1R. Among them, SB-334867 in the lowest effective dose of 3 mg/kg i.p. was most studied, as shown in the model of two-bottle choice using C57BL/6 mice. Moreover, this compound did not affect the reduction of cognitive functions. GSK1059865 was also involved in the selective reduction of ethanol intake, and simultaneously did not alter the consumption of sugar solution. The other group of selective OX2R antagonists, such as TCS-OX2-29 and LSN2424100, was less efficient. In summary, the OX1R antagonists proved to have the potential in AUD therapy, not only through the reduction of ethanol consumption but also in the treatment of coexisting behavioral and physiological disorders, such as insomnia and anxiety.

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Anatomical Study of Intrahemispheric Association Fibers in the Brains of Capuchin Monkeys (Sapajussp.)

BioMed Research International ◽

10.1155/2015/648128 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Kellen Christina Malheiros Borges ◽

Hisao Nishijo ◽

Tales Alexandre Aversi-Ferreira ◽

Jussara Rocha Ferreira ◽

Leonardo Ferreira Caixeta

Keyword(s):

Nonhuman Primates ◽

Evolutionary Process ◽

Anatomical Study ◽

Lateral View ◽

Superior Longitudinal Fasciculus ◽

Cognitive Behaviors ◽

Behavioral Studies ◽

Inferior Longitudinal Fasciculus ◽

Association Fibers ◽

The Brain

Previous studies suggest that the complexity of fiber connections in the brain plays a key role in the evolutionary process of the primate brain and behaviors. The patterns of brain fiber systems have been studied in detail in many nonhuman primates, but not inSapajussp. Behavioral studies indicated thatSapajussp. (bearded capuchins) show highly cognitive behaviors such as tool use comparable to those in other nonhuman primates. To compare the brain fiber systems in capuchins with those in other nonhuman primates and humans, the intrahemispheric fibers systems in 24 cerebral hemispheres ofSapajuswere dissected by a freezing-thawing procedure. Dissection of the hemispheres in lateral view indicated short arcuate fibers, uncinate fasciculus, and inferior longitudinal fasciculus, while that in a medial view indicated short arcuate fibers, the cingulum united with the superior longitudinal fasciculus, and inferior longitudinal fasciculus. The results showed that the fiber systems inSapajusare comparable to those in rhesus and humans, except for a lack of independent superior longitudinal fasciculus and cingulum inSapajus.

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Learning what is irrelevant or relevant: Expectations facilitate distractor inhibition and target facilitation through distinct neural mechanisms

10.1101/565069 ◽

2019 ◽

Cited By ~ 1

Author(s):

Dirk van Moorselaar ◽

Heleen A. Slagter

Keyword(s):

Target Location ◽

Response Times ◽

Relevant Information ◽

Distractor Location ◽

Distractor Inhibition ◽

Distractor Processing ◽

Behavioral Studies ◽

Outstanding Question ◽

Target Locations ◽

The Brain

AbstractIt is well known that attention can facilitate performance by top-down biasing processing of task-relevant information in advance. Recent findings from behavioral studies suggest that distractor inhibition is not under similar direct control, but strongly dependent on expectations derived from previous experience. Yet, how expectations about distracting information influence distractor inhibition at the neural level remains unclear. The current study addressed this outstanding question in three experiments in which search displays with repeating distractor or target locations across trials allowed observers to learn which location to selectively suppress or boost. Behavioral findings demonstrated that both distractor and target location learning resulted in more efficient search, as indexed by faster response times. Crucially, benefits of distractor learning were observed without target location foreknowledge, unaffected by the number of possible target locations, and could not be explained by priming alone. To determine how distractor location expectations facilitated performance, we applied a spatial encoding model to EEG data to reconstruct activity in neural populations tuned to the distractor or target location. Target location learning increased neural tuning to the target location in advance, indicative of preparatory biasing. This sensitivity increased after target presentation. By contrast, distractor expectations did not change preparatory spatial tuning. Instead, distractor expectations reduced distractor-specific processing, as reflected in the disappearance of the Pd ERP component, a neural marker of distractor inhibition, and decreased decoding accuracy. These findings suggest that the brain may no longer process expected distractors as distractors, once it has learned they can safely be ignored.Significance statementWe constantly try hard to ignore conspicuous events that distract us from our current goals. Surprisingly, and in contrast to dominant attention theories, ignoring distracting, but irrelevant events does not seem to be as flexible as is focusing our attention on those same aspects. Instead, distractor suppression appears to strongly rely on learned, context-dependent expectations. Here, we investigated how learning about upcoming distractors changes distractor processing and directly contrasted the underlying neural dynamics to target learning. We show that while target learning enhanced anticipatory sensory tuning, distractor learning only modulated reactive suppressive processing. These results suggest that expected distractors may no longer be considered distractors by the brain once it has learned that they can safely be ignored.

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Behavioral and Neurophysiological Demonstration of a Lateralis Skin Photosensitivity in Larval Sea Lampreys

Journal of Experimental Biology ◽

10.1242/jeb.161.1.97 ◽

1991 ◽

Vol 161 (1) ◽

pp. 97-117 ◽

Cited By ~ 1

Author(s):

MARK RONAN ◽

DAVID BODZNICK

Keyword(s):

Spontaneous Activity ◽

Lateral Line ◽

Lateral Line Nerve ◽

Medial Nucleus ◽

Posterior Lateral Line ◽

Behavioral Studies ◽

Sea Lampreys ◽

Response Thresholds ◽

The Brain ◽

Skin Photosensitivity

Larval lampreys respond to skin illumination with a delayed burst of swimming in an attempt to escape the light. The photoresponse, which is independent of the lateral eyes and pineal organs, is most readily elicited by light shone on the tail. Behavioral studies in larval lampreys demonstrate that photosensory afferents innervating the tail are carried by a trunk lateral line nerve supplying regions caudal to the head. The present results confirm that bilateral transection of this nerve in larval sea lampreys markedly diminishes the photoresponse. The trunk lateral line nerve consists of the recurrent ramus of the anterior lateral line nerve and a ramus of the posterior lateral line nerve. Bilateral transection of the recurrent ramus does not affect the photoresponse, indicating that lateralis photosensory afferents enter the brain via the posterior lateral line nerve and terminate in the medial octavolateralis nucleus. Photosensory units were subsequently recorded in the trunk lateral line nerve, posterior lateral line nerve and the lateral line area of the medulla. Medullary photosensory units were localized to the medial nucleus, previously regarded as the primary mechanosensory nucleus. Photosensory units in lateral line nerves and the brain exhibited low, irregular spontaneous activity and, after latencies of 17–4 s, responded to tail illumination with repeated impulse bursts. Response thresholds were 0.1-0.9 mWcm−2. Responses to sustained illumination were slowly adapting. A skin photosense is thus an additional lateralis modality in lampreys.

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Tissue cyst tropism in Toxoplasma gondii: a comparison of tissue cyst formation in organs of cats, and rodents fed oocysts

Parasitology ◽

10.1017/s0031182097008949 ◽

1997 ◽

Vol 115 (1) ◽

pp. 15-20 ◽

Cited By ~ 52

Author(s):

J. P. DUBEY

Keyword(s):

Toxoplasma Gondii ◽

Cyst Formation ◽

Tissue Cyst ◽

Intermediate Hosts ◽

Mesenteric Lymph Nodes ◽

Marked Contrast ◽

Mesenteric Lymph ◽

Time Period ◽

Rats And Mice ◽

The Brain

The persistence of Toxoplasma gondii tissue cysts in organs of cats (definitive host) and rodents (intermediate hosts) was studied. Nine cats, 12 rats, and 12 mice were fed T. gondii oocysts and their organs were digested in pepsin and then bioassayed for bradyzoites in mice. Of 9 cats killed 37 or 51 days after feeding 102 (2 cats), 103 (3 cats) or 104 (4 cats) oocysts of the VEG strain, tissue cysts were found in each cat; in the tongue of 9, in the heart of 5, in the brain of 4, and in the eyes of 1 cat. The dose had no effect on the distribution of tissue cysts in cats. Twelve rats were each fed 105 oocysts of the VEG strain of T. gondii and killed 21, 29, 64 or 237 days later. At each time-period, 11 tissues of 3 rats were pooled and bioassayed in mice. Tissue cysts were found in the brain, skeletal muscle, heart and kidneys of rats at each killing time; in the lungs, intestines, and mesenteric lymph nodes in 3 of 4 instances; in the tongue, liver, and eyes in 2 instances and in the spleen in 1 instance. Also, using the same procedures and sampling the same 11 tissues as used for rats, tissue cysts were seen in all organs except in the tongue and liver of 3 mice killed on day 82 after feeding the VEG strain. In 9 mice (3 with each strain) fed oocysts of the ME-49, GT-1, or P89 T. gondii strain and killed 62–130 days later, tissue cysts were found consistently only in the brain. Thus, in rats and mice, most tissue cysts were found in the brain and rarely in the tongue. This was in marked contrast to the distribution of tissue cysts in cats.

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Time course of spatiotopic updating across saccades

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812210116 ◽

2019 ◽

Vol 116 (6) ◽

pp. 2027-2032 ◽

Cited By ~ 6

Author(s):

Jasper H. Fabius ◽

Alessio Fracasso ◽

Tanja C. W. Nijboer ◽

Stefan Van der Stigchel

Keyword(s):

Eye Movements ◽

Visual System ◽

Eye Movement ◽

Time Course ◽

Saccadic Eye Movements ◽

Oculomotor System ◽

Stimulus Onset ◽

Oculomotor Behavior ◽

Behavioral Studies ◽

The Brain

Humans move their eyes several times per second, yet we perceive the outside world as continuous despite the sudden disruptions created by each eye movement. To date, the mechanism that the brain employs to achieve visual continuity across eye movements remains unclear. While it has been proposed that the oculomotor system quickly updates and informs the visual system about the upcoming eye movement, behavioral studies investigating the time course of this updating suggest the involvement of a slow mechanism, estimated to take more than 500 ms to operate effectively. This is a surprisingly slow estimate, because both the visual system and the oculomotor system process information faster. If spatiotopic updating is indeed this slow, it cannot contribute to perceptual continuity, because it is outside the temporal regime of typical oculomotor behavior. Here, we argue that the behavioral paradigms that have been used previously are suboptimal to measure the speed of spatiotopic updating. In this study, we used a fast gaze-contingent paradigm, using high phi as a continuous stimulus across eye movements. We observed fast spatiotopic updating within 150 ms after stimulus onset. The results suggest the involvement of a fast updating mechanism that predictively influences visual perception after an eye movement. The temporal characteristics of this mechanism are compatible with the rate at which saccadic eye movements are typically observed in natural viewing.

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Changes in activity rates in the cherry shrimp Neocaridina davidi Bouvier, 1904 (Decapoda: Caridea: Atyidae) in response to concentrations of neuropeptides and glucose

Journal of Crustacean Biology ◽

10.1093/jcbiol/ruz059 ◽

2019 ◽

Vol 39 (6) ◽

pp. 689-694

Author(s):

Joseph S Stout ◽

Carla L Granda ◽

Molly L Mancuso

Keyword(s):

Food Pellet ◽

Inhibitory Effect ◽

Dopaminergic Drugs ◽

Behavioral Studies ◽

Seeking Behavior ◽

Food Seeking ◽

And Behavior ◽

Rats And Mice ◽

Reduced Activity ◽

Over Time

Abstract Although behavioral studies of whole animals are usually undertaken on rats and mice, studies in crustaceans offer an alternative group that provides new evolutionary insights into the relationship between physiology and behavior. In the cherry shrimp Neocaridina davidi (Bouvier, 1904), food-seeking movement increases in response to glutamate (MSG), decreases when exposed to dopamine, and increases when exposed to glucose. Activity of shrimp individuals was observed in 4l tanks over twenty minutes after individuals were exposed to treatments applied directly into the water. Glutamate-stimulated seeking behavior was statistically similar to seeking behavior after exposure to food pellet filtrate. Glucose also stimulated seeking behavior, but with a reduction over time, whereas MSG-stimulated seeking behavior increased over time. Insulin reduced activity but showed no effect when paired with glucose, whereas dopamine increased activity when paired with glucose. This was contrary to the reduced activity observed when dopamine was paired with MSG. The decrease in activity after exposure to dopamine also contrasts with vertebrate (rat) models where dopaminergic drugs such as caffeine and cocaine are stimulants. The stimulatory effect of dopamine paired with glucose was unexpected given its inhibitory effect on its own or when paired with MSG. This crustacean-based model aims to give new insights regarding the role of inhibitory and stimulatory neurotransmitters on the behavior of whole crustacean individuals. These mechanisms show different results than predicted by vertebrate models, implying either differences in underlying physiology, problems with the vertebrate models, or both.

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Opposed optimal strategies of weighting somatosensory inputs for planning reaching movements toward visual and proprioceptive targets

Journal of Neurophysiology ◽

10.1152/jn.00857.2013 ◽

2014 ◽

Vol 112 (9) ◽

pp. 2290-2301 ◽

Cited By ~ 12

Author(s):

Jean Blouin ◽

Anahid H. Saradjian ◽

Nicolas Lebar ◽

Alain Guillaume ◽

Laurence Mouchnino

Keyword(s):

Visual Feedback ◽

Sensory Modality ◽

Optimal Strategies ◽

Neural Correlates ◽

Movement Planning ◽

Reaching Movements ◽

Behavioral Studies ◽

Somatosensory Input ◽

Visual Targets ◽

The Brain

Behavioral studies have suggested that the brain uses a visual estimate of the hand to plan reaching movements toward visual targets and somatosensory inputs in the case of somatosensory targets. However, neural correlates for distinct coding of the hand according to the sensory modality of the target have not yet been identified. Here we tested the twofold hypothesis that the somatosensory input from the reaching hand is facilitated and inhibited, respectively, when planning movements toward somatosensory (unseen fingers) or visual targets. The weight of the somatosensory inputs was assessed by measuring the amplitude of the somatosensory evoked potential (SEP) resulting from vibration of the reaching finger during movement planning. The target sensory modality had no significant effect on SEP amplitude. However, Spearman's analyses showed significant correlations between the SEPs and reaching errors. When planning movements toward proprioceptive targets without visual feedback of the reaching hand, participants showing the greater SEPs were those who produced the smaller directional errors. Inversely, participants showing the smaller SEPs when planning movements toward visual targets with visual feedback of the reaching hand were those who produced the smaller directional errors. No significant correlation was found between the SEPs and radial or amplitude errors. Our results indicate that the sensory strategy for planning movements is highly flexible among individuals and also for a given sensory context. Most importantly, they provide neural bases for the suggestion that optimization of movement planning requires the target and the reaching hand to both be represented in the same sensory modality.

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What can developmental disorders tell us about the neurocomputational constraints that shape development? The case of Williams syndrome

Development and Psychopathology ◽

10.1017/s0954579403000476 ◽

2003 ◽

Vol 15 (4) ◽

pp. 969-990 ◽

Cited By ~ 40

Author(s):

ANNETTE KARMILOFF–SMITH ◽

MICHAEL THOMAS

Keyword(s):

Williams Syndrome ◽

Developmental Disorders ◽

Genetic Disorders ◽

Actual Process ◽

Cognitive Domains ◽

Behavioral Studies ◽

Starting Point ◽

Cognitive Modularity ◽

Genetically Determined ◽

The Brain

The uneven cognitive phenotype in the adult outcome of Williams syndrome has led some researchers to make strong claims about the modularity of the brain and the purported genetically determined, innate specification of cognitive modules. Such arguments have particularly been marshaled with respect to language. We challenge this direct generalization from adult phenotypic outcomes to genetic specification and consider instead how genetic disorders provide clues to the constraints on plasticity that shape the outcome of development. We specifically examine behavioral studies, brain imaging, and computational modeling of language in Williams syndrome but contend that our theoretical arguments apply equally to other cognitive domains and other developmental disorders. While acknowledging that selective deficits in normal adult patients might justify claims about cognitive modularity, we question whether similar, seemingly selective deficits found in genetic disorders can be used to argue that such cognitive modules are prespecified in infant brains. Cognitive modules are, in our view, the outcome of development, not its starting point. We note that most work on genetic disorders ignores one vital factor, the actual process of ontogenetic development, and argue that it is vital to view genetic disorders as proceeding under different neurocomputational constraints, not as demonstrations of static modularity.

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Two-Photon Microscopy as a Tool to Study Blood Flow and Neurovascular Coupling in the Rodent Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.196 ◽

2012 ◽

Vol 32 (7) ◽

pp. 1277-1309 ◽

Cited By ~ 231

Author(s):

Andy Y Shih ◽

Jonathan D Driscoll ◽

Patrick J Drew ◽

Nozomi Nishimura ◽

Chris B Schaffer ◽

...

Keyword(s):

Blood Flow ◽

Laser Scanning ◽

Vascular System ◽

Neurovascular Coupling ◽

Laser Scanning Microscopy ◽

Small Scale ◽

Two Photon Microscopy ◽

Two Photon ◽

Rats And Mice ◽

The Brain

The cerebral vascular system services the constant demand for energy during neuronal activity in the brain. Attempts to delineate the logic of neurovascular coupling have been greatly aided by the advent of two-photon laser scanning microscopy to image both blood flow and the activity of individual cells below the surface of the brain. Here we provide a technical guide to imaging cerebral blood flow in rodents. We describe in detail the surgical procedures required to generate cranial windows for optical access to the cortex of both rats and mice and the use of two-photon microscopy to accurately measure blood flow in individual cortical vessels concurrent with local cellular activity. We further provide examples on how these techniques can be applied to the study of local blood flow regulation and vascular pathologies such as small-scale stroke.

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