Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction.
Proceedings of the National Academy of Sciences. 2005-08-02; 102(32): 11533-11538
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1. Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11533-8. Epub 2005 Aug 2.
Gene expression evidence for remodeling of lateral hypothalamic circuitry in
Ahmed SH(1), Lutjens R, van der Stap LD, Lekic D, Romano-Spica V, Morales M, Koob
GF, Repunte-Canonigo V, Sanna PP.
(1)Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
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.
PMID: 16076954 [Indexed for MEDLINE]