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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...