Effect of Prolonged Exposure to Short Daylight and a Tryptophan Hydroxylase Inhibitor on the Behavior and Brain Serotonin System in Danio rerio.

We studied the effect of reduced tryptophan hydroxylase (TPH) activity and short daylight exposure on the behavior and the 5-HT system of the brain in D. rerio. Male and female D. rerio were exposed for 30 days to standard (12:12 h light:dark) and short (4:20 h light:dark) photoperiods in the presence or absence of TPH inhibitor (p-chlorophenylalanine, pCPA, 5 mg/liter). On day 31, the fish behavior in the "novel tank diving" test, their sex and body weight were determined, and the levels of pCPA, 5-HT, and its metabolite 5-HIAA were measured by HPLC; the levels of the key genes encoding metabolism enzymes (Tph1a, Tph1b, Tph2, and Mao) and receptors of 5-HT (Htr1aa, Htr2aa) were assessed by real-time PCR with reverse transcription. The short daylight exposure caused masculinization of females, reduced body weight, and motor activity in the "novel tank diving" test, but did not affect the 5-HT system of the brain. Long-term pCPA treatment had no effect on sex and body weight, significantly reduced the 5-HIAA level, but increased Tph1a and Tph2 gene expression in the brain. No effects of the interaction of short daylight and pCPA exposure on the sex, body weight, behavior, and 5-HT system of the brain were found. Thus, a moderate decrease in TPH activity cannot potentiate the negative effects of short daylight exposure on the sex, body weight, behavior, and 5-HT system of D. rerio.

Long-Term Continuous Computer Registration and Analysis of Motor Activity of a Group of Zebrafish Danio rerio.

A new algorithm for long-term continuous computer recording and analysis of motor activity of a group of zebrafish in the home tank has been developed. The movements of a group of Danio rerio during the entire light period and for several days are recorded at a frequency of 1 frame/sec in the form of short (15 min) files. Then these files are analyzed by the unique DanioStudo software, which, using a threshold algorithm and appropriate masks, calculates for each frame the sum of pixels associated with fish (the sum of fish silhouettes), and for two consecutive frames, the sum of altered pixels (the sum of altered fish silhouettes). The following indexes are calculated: the rate of sum of silhouettes alteration as the ratio of the sum of altered silhouettes to the sum of silhouettes (1) and the time spent in the selected area of the home tank as the ratio of the sum of silhouettes in this area to the sum of silhouettes in the entire tank (2). The mean rate of silhouette alteration correlates to the length of the path travelled by the fish and, therefore, serves as a correct measure of the motor activity of a group of fish. Using these algorithms, completely new data were obtained: it was shown that the motor activity of fish remains constant throughout the entire light period, but depends on the size of the home tank. The proposed approach, together with the DanioStudio software, can be effective in studying the dynamics of changes in the behavior of fish under long-term exposure to short daylight, drugs and toxic substances.

Effect of Short Photoperiod on the Behavior and Brain Serotonin System in Zebrafish Danio rerio.

Reduced daylight duration causes the development of seasonal affective disorder (SAD; depression-like disorders characterized by depressed mood, apathy, bulimia, and weight gain) in sensitive individuals. Neurotransmitter serotonin (5-HT) is involved in the mechanism of SAD. Zebrafish (D. rerio) is a promising model for translational studies. We studied changes in the behavior, content of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the expression of genes encoding the key enzymes of 5-HT metabolism, tryptophan hydroxylases TPH1A, TPH1B, TPH2, monoamine oxidase (MAO), 5-HT transporter, and 5-HT1A and 5-HT2A receptors in the brain of zebrafish reared for 60 days under short (04:20 h) compared to those reared at normal (12:12 h) photoperiod. Exposure to short photoperiod decreased locomotor activity in the novel tank diving test, increased the level 5-HIAA, and reduced the level of Mao gene mRNA, but did not affect the level of 5-HT and expression of Tph1a, Tph1b, Tph2, Slc6a4a (transporter), Htr1aa, and Htr2aa (receptors) genes. Thus, zebrafish can be used as a promising model to study the involvement of 5-HT in the SAD mechanism.

Effect of Photoperiod and Lethal Yellow Mutation on Depression-Like Behavior and Expression of Proinflammatory Cytokines in the Hypothalamus in Mice.

We studied the influence of obesity caused by lethal yellow (AY) mutation in the agouti gene, short photoperiod (4/20 h light/darkness), and combination of these factors on depressive-like behavior in the forced swimming test and expression of genes encoding proinflammatory cytokines in the hypothalamus of heterozygous male C57Bl/6-AY/a mice and their wild-type littermate controls (C57Bl/6-a/a). It was shown that AY mutation as well as short photoperiod increased depressive-like behavior in mice. No effect of the interaction of AY mutation and photoperiod on immobility in the forced swimming test was revealed. In wild-type mice, increased depressive-like behavior caused by short photoperiod was accompanied by enhanced expression of Tnf gene. Exposure to short daylight increased the expression of Nos2.

Inhibitor of Striatal-Enriched Protein Tyrosine Phosphatase, 8-(Trifluoromethyl)-1,2,3,4,5-Benzopentathiepin-6-Amine hydrochloride (TC-2153), Produces Antidepressant-Like Effect and Decreases Functional Activity and Protein Level of 5-HT2A Receptor in the Brain.

The serotoninergic 5-HT2A receptor is involved in the mechanism of depression and antidepressant drugs action. Earlier we showed that striatal-enriched protein tyrosine phosphatase (STEP) inhibitor - 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) affects both the brain serotoninergic system and the brain-derived neurotropic factor that are known to be involved in the psychopathology of depression. In the present study we investigated the effects of chronic TC-2153 administration on behavior in the standard battery of tests as well as the effects of acute and chronic TC-2153 treatment on the brain 5-HT2A receptors in mice. We obtained a prominent antidepressant-like effect of chronic TC-2153 treatment in the forced swim test without any adverse side effects on locomotor activity, anxiety, exploration, motor skill and obsessive-compulsive-like behavior. Moreover, both acute and chronic TC-2153 administration inhibited the functional activity of 5-HT2A receptors estimated by the number of 2,5-dimethoxy-4-iodoamphetamine (DOI, agonist of 5-HT2A receptors)-induced head-twitches. TC-2153 treatment also attenuated the DOI-induced c-fos expression in cortical and hippocampal neurons and reduced the 5-HT2A receptor protein level in the hippocampus and frontal cortex, but not in the striatum. Taken together, our combined data demonstrate that the antidepressant effect of STEP inhibitor TC-2153 could be mediated by its inhibitory properties towards the 5-HT2A receptor-mediated signaling.