Gene expression changes following extinction testing in a heroin behavioral incubation model.

Full Abstract

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. CONCLUSION: 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.

Author information

Author/s: Kuntz-Melcavage, Kara L (KL); Brucklacher, Robert M (RM); Grigson, Patricia S (PS); Freeman, Willard M (WM); Vrana, Kent E (KE);

Affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA. kuntzmelcavagkl(-atsign-)ninds.nih.gov

Grants: DA021450 (Agency:NIDA NIH HHS) ; DA12473 (Agency:NIDA NIH HHS) ; DA13770 (Agency:NIDA NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: BMC neuroscience (BMC Neurosci), published in England. (Language: eng)

Reference: 2009-; vol 10 (issue ) : pp 95

Dates: Created 2009/08/26; Completed 2009/09/24;

PMID: 19664213, status: MEDLINE (last retrieval date: 9/24/2009, IMS Date: )

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