Gene expression changes following extinction testing in a heroin behavioral incubation model.
BACKGROUND
A number of gene expression studies have investigated changes induced by drug exposure, but few reports describe changes that persist following relapse. In this study, genome-wide analysis of gene expression was conducted following an extinction session (90 min) in rats that expressed behavioral incubation of heroin-seeking and goal-directed behavior. As an important modulator of goal-directed behavior, the medial prefrontal cortex (mPFC) was the target of genomic analysis. Rats were trained to self-administer heroin during 3 h daily sessions for 14 d. Following the self-administration period, rats were reintroduced to the self-administration chambers for a 90-minute extinction session in which they could seek heroin, but received none. Extinction sessions were conducted on groups after either 1 d or 14 d of drug-free enforced abstinence to demonstrate behavioral incubation.


RESULTS
Behavioral data demonstrated incubation (increased expression) of heroin-seeking and goal-directed behavior after the 14 d abstinent period. That is, following 14 d of enforced abstinence, animals displayed heightened drug-seeking behavior when returned to the environment where they had previously received heroin. This increased drug-seeking took place despite the fact that they received no drug during this extinction session. Whole genome gene expression analysis was performed and results were confirmed by quantitative real-time PCR (RT-qPCR). Microarrays identified 66 genes whose expression was identified as changed by at least 1.4 fold (p < 0.02) following 14 d of abstinence and the 90-minute extinction session compared to the saline treated controls. Orthogonal confirmation by RT-qPCR demonstrated significant alterations in bdnf, calb1, dusp5, dusp6, egr1, npy, rgs2.


CONCLUSIONS
Ontological analysis indicates that several of the genes confirmed to be changed are important for neuroplasticity, and through that role may impact learning and behavior. The importance of drug-seeking behavior and memory of previous drug-taking sessions suggest that such genes may be important for relapse. The global gene expression analysis adds to the knowledge of heroin-induced changes and further highlights similarities between heroin and other drugs of abuse.
Kuntz-Melcavage
Kara L
KL
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA. kuntzmelcavagkl@ninds.nih.gov
Brucklacher
Robert M
RM
Grigson
Patricia S
PS
Freeman
Willard M
WM
Vrana
Kent E
KE
D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics; D003216:Conditioning, Operant; D005108:Extinction, Psychological / Q000502:physiology*; D020869:Gene Expression Profiling; D003932:Heroin / Q000008:administration & dosage; D006556:Heroin Dependence / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D017397:Prefrontal Cortex / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012646:Self Administration; D015854:Up-Regulation / Q000235:genetics
D009419:Nerve Tissue Proteins; D003932:Heroin