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A major hindrance for the development of psychiatric drugs is the prediction of how treatments can alter complex behaviors in assays which have good throughput and physiological complexity. Here we report the development of a medium-throughput screen for drugs which alter anxiety-like behavior in adult zebrafish. The observed phenotypes were clustered according to shared behavioral effects. This barcoding procedure revealed conserved functions of anxiolytic, anxiogenic and psychomotor stimulating drugs and predicted effects of poorly characterized compounds on anxiety. Moreover, anxiolytic drugs all decreased, while anxiogenic drugs increased, serotonin turnover. These results underscore the power of behavioral profiling in adult zebrafish as an approach which combines throughput and physiological complexity in the pharmacological dissection of complex behaviors.

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Adenosinergic systems have been implicated in anxiety-like states, as caffeine can induce a state of anxiety in human beings. Caffeine is an antagonist at A 1 and A 2 adenosine receptors but it remains unclear whether anxiety is mediated by one or both of these. As the adenosinergic system is rather conserved, we opted to pursue these questions using zebrafish, a widely used model organism in genetics and developmental biology. Zebrafish adenosine 1. 2A.1 and 2A.2 receptors conserve histidine residues in TM6 and TM7 that are responsible for affinity in bovine A1 receptor. We investigated the effects of caffeine, PACPX (an A 1 receptor antagonist) and 1,3-dimethyl-1-propargylxanthine (DMPX) (an A 2 receptor antagonist) on anxiety-like behaviour and locomotor activity of zebrafish in the scototaxis test as well as evaluated the effects of these drugs on pigment aggregation. Caffeine increased anxiety at the dose of 100 mg ⁄ kg, while locomotion at the dose of 10 mg ⁄ kg was increased. Both doses of 10 and 100 mg ⁄ kg induced pigment aggregation. PACPX, on the other hand, increased anxiety at a dose of 6 mg ⁄ kg and induced pigment aggregation at the doses of 0.6 and 6 mg ⁄ kg, but did not produce a locomotor effect. DMPX, in turn, increased locomotion at the dose of 6 mg ⁄ kg but did not produce any effect on pigment aggregation or anxiety-like behaviour. These results indicate that blockade of A 1 -R, but not A 2 -R, induces anxiety and autonomic arousal, while the blockade of A 2 -R induces hyperlocomotion. Thus, as in rodents, caffeine's anxiogenic and arousing effects are probably mediated by A 1 receptors in zebrafish and its locomotor activating effect is probably mediated by A 2 receptors.Several lines of evidence implicate adenosine receptors in the modulation of anxiety-like states and autonomic arousal. Caffeine, a non-selective adenosine A 1 and A 2A and A 2B receptor antagonist [1,2], increases anxiety in rodents [3][4][5][6][7][8] and humans beings [9]; it is uncertain whether these effects can been ascribed to the disinhibition of adenosinergic tonus at A 1 or A 2A receptors [9]. Administration of adenosine A 1 receptor agonists produces anxiolytic-like effects in rodents, while the adenosine A 1 -R antagonists produce anxiogeniclike effects [10][11][12]. The association between A 1 -Rs and anxiety is also seen regarding the anxiolytic effect of ethanol in the elevated plus-maze, because administration of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a A 1 -R antagonist (but not ZM241,385, a A 2A -R antagonist) attenuates the anxiolytic-like response to ethanol [12]. Moreover, the administration of 2-chloro-N6-cyclopentyladenosine (CCPA), an A 1 -R agonist, during ethanol withdrawal produces an anxiolyticlike effect that is reversed by DPCPX [13]. In CD1 mice, administration of the A 1 -R agonist CCPA is anxiolytic in the light ⁄ dark box test and in the elevated plus-maze, while the A 1 -R antagonist cyclopentyltheopylline (CPT) had an anxiogenic effect [11]. Mice knocked out for the A 1 rec...

ObjectiveThe recognition of the limits between normal and pathological aging is essential to start preventive actions. The aim of this paper is to compare the Cambridge Neuropsychological Test Automated Battery (CANTAB) and language tests to distinguish subtle differences in cognitive performances in two different age groups, namely young adults and elderly cognitively normal subjects.MethodWe selected 29 young adults (29.9±1.06 years) and 31 older adults (74.1±1.15 years) matched by educational level (years of schooling). All subjects underwent a general assessment and a battery of neuropsychological tests, including the Mini Mental State Examination, visuospatial learning, and memory tasks from CANTAB and language tests. Cluster and discriminant analysis were applied to all neuropsychological test results to distinguish possible subgroups inside each age group.ResultsSignificant differences in the performance of aged and young adults were detected in both language and visuospatial memory tests. Intragroup cluster and discriminant analysis revealed that CANTAB, as compared to language tests, was able to detect subtle but significant differences between the subjects.ConclusionBased on these findings, we concluded that, as compared to language tests, large-scale application of automated visuospatial tests to assess learning and memory might increase our ability to discern the limits between normal and pathological aging.

Acute stress is an important factor in the development of anxiety disorders. Zebrafish are an organism model widely used by studies that aim to describe the events in the brain that control stress-elicited anxiety. the goal of the current study was to evaluate the pattern of cell activation in the telencephalon of adult zebrafish and the role of the GABAergic system on the modulation of anxiety-like behavior evoked by acute restraint stress. Zebrafish that underwent acute restraint stress presented decreased expression of the c-fos protein in their telencephalon as well as a significant decrease in GABA release. The data also supports that decreased GABA levels in zebrafish brains have diminished the activation of GABAA receptors eliciting anxiety-like behavior. Taken together these findings have helped clarify a neurochemical pathway controlling anxiety-like behavior evoked by acute stress in zebrafish while also opening the possibility of new perspective opportunities to use zebrafish as an animal model to test anxyolitic drugs that target the GABAergic system. open Scientific RepoRtS | (2020) 10:5551 | https://doi.

Repair of injured tendon is a very slow process and involves the release of many molecules, including nitric oxide. We investigate the influence of local nitrergic inhibition in histological and functional recovery of injured Achilles tendon. A standard murine model of tendon injury by rupture was used. The animals were divided into three experimental groups: control, injury + vehicle (normal saline) and injury + Nω-nitro-L-arginine methyl ester (L-NAME). The products were injected into the paratendinous region every 2 days and body weight gain and Achilles functional index (AFI) were evaluated on days 0, 7, 14 and 21 after tendon injury. On day 21 post-injury, the animals were killed to evaluate nitric oxide production and tissue organization. We observed that tendon surgical division led to increased tissue nitrite levels, which were reduced in L-NAME-treated rats. The AFI revealed functional recovery of L-NAME-treated animals on day 21 post-injury, which was not observed in the saline-treated group. Microscopic analysis of hematoxylin-eosin staining and collagen autofluorescence showed that L-NAME-treated rats had more aligned areas of collagen fibers and that the diameter of newly organized collagen in this group was also greater than that in the vehicle-treated one. We demonstrate that local treatment with L-NAME significantly improves the functional parameters and accelerates histomorphological recovery.