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Different effects of methylphenidate and atomoxetine on the behavior and brain transcriptome of zebrafish.

ABSTRACT: Attention deficit-hyperactivity disorder (ADHD) is a prevalent neuropsychiatric disorder found in children. It is characterized by inattention, hyperactivity, and impulsivity. Methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed for the treatment of ADHD. In the present study, we examined the behavioral and brain transcriptome changes in MPH-treated and ATX-treated zebrafish. In behavioral analysis, zebrafish showed opposite response to each treatment. MPH-treated fish showed higher anxiety-like behavior while ATX-treated fish showed lower anxiety-like behavior. Further, we performed RNA sequencing analysis of zebrafish brain to elucidate the underlying biological pathways associated with MPH and ATX treatment. Interestingly, we found that shared differentially expressed genes in MPH-treated and ATX-treated fish were instrumental in cholesterol biosynthesis pathway and were regulated in opposite manner. Our findings highlight the contrast between MTH and ATX, and may suggest the alterations in clinical practice for these medications and drug development for ADHD.

SUBMITTER: Suzuki S

PROVIDER: S-EPMC7203832 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Different effects of methylphenidate and atomoxetine on the behavior and brain transcriptome of zebrafish.

Suzuki Shiho S Kimura Ryo R Maegawa Shingo S Nakata Masatoshi M Hagiwara Masatoshi M

Molecular brain 20200506 1

Attention deficit-hyperactivity disorder (ADHD) is a prevalent neuropsychiatric disorder found in children. It is characterized by inattention, hyperactivity, and impulsivity. Methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed for the treatment of ADHD. In the present study, we examined the behavioral and brain transcriptome changes in MPH-treated and ATX-treated zebrafish. In behavioral analysis, zebrafish showed opposite response to each treatment. MPH-treated fish showed high ...[more]

PMID: 32375837

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Project description:BackgroundAttention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown.MethodsTo investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28-55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule.ResultsCompared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains.ConclusionsThe SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD.

Project description:The synthetic estrogen 17α-ethinylestradiol (EE2) is an endocrine disrupting compound of concern due to its persistence and widespread presence in the aquatic environment. Effects of developmental exposure to low concentrations of EE2 in fish on reproduction and behavior not only persisted to adulthood, but have also been observed to be transmitted to several generations of unexposed progeny. To investigate the possible biological mechanisms of the persistent anxiogenic phenotype, we exposed zebrafish embryos for 80 days post fertilization to 0, 3, and 10 ng/L EE2 (measured concentrations 2.14 and 7.34 ng/L). After discontinued exposure, the animals were allowed to recover for 120 days in clean water. Adult males and females were later tested for changes in stress response and shoal cohesion, and whole-brain gene expression was analyzed with RNA sequencing. The results show increased anxiety in the novel tank and scototaxis tests, and increased shoal cohesion in fish exposed during development to EE2. RNA sequencing revealed 34 coding genes differentially expressed in male brains and 62 in female brains as a result of EE2 exposure. Several differences were observed between males and females in differential gene expression, with only one gene, sv2b, coding for a synaptic vesicle protein, that was affected by EE2 in both sexes. Functional analyses showed that in female brains, EE2 had significant effects on pathways connected to the circadian rhythm, cytoskeleton and motor proteins and synaptic proteins. A large number of non-coding sequences including 19 novel miRNAs were also differentially expressed in the female brain. The largest treatment effect in male brains was observed in pathways related to cholesterol biosynthesis and synaptic proteins. Circadian rhythm and cholesterol biosynthesis, previously implicated in anxiety behavior, might represent possible candidate pathways connecting the transcriptome changes to the alterations to behavior. Further the observed alteration in expression of genes involved in synaptogenesis and synaptic function may be important for the developmental modulations resulting in an anxiety phenotype. This study represents an initial survey of the fish brain transcriptome by RNA sequencing after long-term recovery from developmental exposure to an estrogenic compound.

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Different effects of methylphenidate and atomoxetine on the behavior and brain transcriptome of zebrafish.

Publications

Different effects of methylphenidate and atomoxetine on the behavior and brain transcriptome of zebrafish.

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