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The use of zebrafish reward mutants to search for novel transcripts mediating the behavioral effects of amphetamine

ABSTRACT: Addiction is a pathological dysregulation of brain reward systems, determined by several complex genetic pathways. The conditioned place preference (CPP) test provides an evaluation of the effects of drugs in animal models, allowing the investigation of substances at a biologically relevant level with respect to reward. Our lab has previously reported the development of a reliable CPP paradigm for zebrafish. Here, this CPP test was used to isolate a dominant ENU-induced mutant, no addiction (naddne3256), which fails to respond to amphetamine, and which we used as an entry point towards identifying the behaviorally- relevant transcriptional response to amphetamine. Using microarray technology, we compare the wildtype with the mutant response to the drug, we compare the transcriptomes of the wildtype and mutants without drug and we also compared the transcriptomes of wildtype fish with the drug and wildtype fish without the drug. Through the combination of microarray experiments comparing the adult brain transcriptome of mutant and wild-type siblings under normal conditions, as well as their response to amphetamine, we identified genes that correlate with the mutants’ altered CPP behavior. In addition to pathways classically involved in reward, this gene set shows a striking enrichment in transcription factor-encoding genes classically involved in brain development, which later appear to be re-used within the adult brain. We selected a subset of them for validation by quantitative PCR and in situ hybridization, revealing that specific brain areas responding to the drug through these transcription factors include domains of ongoing adult neurogenesis. Finally, network construction revealed functional connections between several of these genes. Together, our results identify a new network of coordinated gene regulation that influences or accompanies amphetamine-triggered CPP behavior and that may underlie the susceptibility to addiction.

ORGANISM(S): Danio rerio

PROVIDER: GSE14399 | GEO | 2009/01/30

SECONDARY ACCESSION(S): PRJNA111377

REPOSITORIES: GEO

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Project description:Drug-induced alterations in transcriptional regulation play a central role in establishing the persistent neuroplasticities that occur during drug addiction. Additionally, changes in gene expression associated with drug administration provide valuable insight into the molecular basis of drug abuse. The molecular mechanisms that underlie susceptibility to psychostimulant addiction remain unknown. Identifying the common gene transcriptional responses to psychostimulants can provide a mechanistic insight to elucidate the molecular nature of drug dependence. Male Wistar rats (4 weeks old) were acclimatized for a week to their housing conditions prior to experiments. Thereafter, they were divided into two groups: (cohort 1) 4 groups of rats (n=12 rats per group) given saline only (i.p., "drug-naive" rats); and (cohort 2): 3 groups of rats given either methamphetamine, amphetamine or methylphenidate (5 mg/kg,i.p., M-CM-"M-bM-^BM-,M-EM-^Sdrug-pretreated") for 7 days (2x daily) prior to behavioral assays. Conditioned place preference (CPP) tests were conducted a day after the final drug administration. Rats which showed CPP were evaluated for self-administration of the psychostimulants. [Cohort 1] A day after the final self-administration test, brains of 2-3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 5 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-CM-^BM-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from 2-5 animals per group. [Cohort 2] A day after the final self-administration test, brains of 3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 3 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from three animals per group.

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The use of zebrafish reward mutants to search for novel transcripts mediating the behavioral effects of amphetamine

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