Dataset Information

Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction.

ABSTRACT: By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy.

SUBMITTER: Ahmed SH

PROVIDER: S-EPMC1183574 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction.

Ahmed Serge H SH Lutjens Robert R van der Stap Lena D LD Lekic Dusan D Romano-Spica Vincenzo V Morales Marisela M Koob George F GF Repunte-Canonigo Vez V Sanna Pietro Paolo PP

Proceedings of the National Academy of Sciences of the United States of America 20050802 32

By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dc ...[more]

PMID: 16076954

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Project description:Animal models of drug use have investigated possible mechanisms governing human substance use traits for over 100 years. Most cross-species research on drug use/addiction examines behavioral overlap, but studies assessing neuromolecular (e.g. RNA) correspondence are lacking. Our study utilized transcriptome-wide data from the hippocampus and ventral tegmental area (VTA)/midbrain from a total of 35 human males with cocaine use disorder/controls and 49 male C57BL/6J cocaine/saline administering/exposed mice. We hypothesized differential expressed genes and systems of co-expressed genes (gene networks) would show appreciable overlap across mouse cocaine self-administration and human cocaine use disorder. We found modest, but significant relationships between differentially expressed genes associated with cocaine self-administration (short access) and cocaine use disorder within reward circuitry. Differentially expressed genes underlying models of acute cocaine exposure (cocaine), context re-exposure and cocaine + context re-exposure were not consistently associated with human CUD across brain regions. Investigating systems of co-expressed genes, we found several validated gene networks with weak to moderate conservation between cocaine/saline self-administering mice and disordered cocaine users/controls. The most conserved hippocampal and VTA gene networks demonstrated substantial overlap (2029 common genes) and included both novel and previously implicated targets for cocaine use/addiction. Lastly, we conducted (expression-based) phenome-wide association studies of the nine common hub genes across conserved gene networks. Common hub genes were associated with dopamine/serotonin function, cocaine self-administration and other relevant mouse traits. Overall, our study pinpointed and characterized conserved brain-related RNA patterns across mouse cocaine self-administration and human cocaine use disorder. We offer recommendations for future research and add to the dialogue surrounding pre-clinical animal research for human disease.

Dataset Information

Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction.

Publications

Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction.

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