Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

Abstract

Rationale-Alterations in the activity of the prefrontal and orbitofrontal cortices of cocaine addicts have been linked with re-exposure to cocaine-associated stimuli. Objectives Using an animal model of relapse to cocaine seeking, the present study investigated the expression patterns of four different activity-regulated genes within prefrontal cortical brain regions after 22 h or 15 days of abstinence during context-induced relapse.Materials and methods-Rats self-administered cocaine or received yoked-saline for 2 h/day for 10 days followed by 22 h or 2 weeks of abstinence when they were re-exposed to the selfadministration chamber with or without levers available to press for 1 h. Brains were harvested and sections through the prefrontal cortex were processed for in situ hybridization using radioactive oligonucleotide probes encoding c-fos, zif/268, arc, and bdnf.Results-Re-exposure to the chamber in which rats previously self-administered cocaine but not saline, regardless of lever availability, increased the expression of all genes in the medial prefrontal and orbitofrontal cortices at both time points with one exception: bdnf mRNA was significantly increased in the medial prefrontal cortex at 22 h only if levers previously associated with cocaine delivery were available to press. Furthermore, re-exposure of rats to the chambers in which they received yoked saline enhanced both zif/268 and arc expression selectively in the orbito-frontal cortex after 15 days of abstinence.Correspondence to: J. F. McGinty. HHS Public AccessAuthor manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2017 May 22. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptConclusions-These results support convergent evidence that cocaine-induced changes in the prefrontal cortex are important in regulating drug seeking following abstinence and may provide additional insight into the molecular mechanisms involved in these processes. KeywordsAddiction; Arc; BDNF; c-fos; Relapse; zif/268; Self-administration; Abstinence; ExtinctionRelapse to drug seeking and taking in addicted humans is often triggered by re-exposure to environmental cues previously associated with the drug (Ehrman et al. 1992). Similarly, in animal studies, during chronic drug self-administration, the drug-paired environment acquires conditioned reinforcing properties that trigger drug-seeking behavior upon reexposure to the context following forced abstinence (Crombag and Shaham 2002;Fuchs et al. 2005Fuchs et al. , 2006. Thus, like other forms of learning, relapse to drug-seeking involves the formation and retrieval of instrumental memories (Hyman 2005). A major question in addiction research is whether the neural substrates underlying drug-seeking involve the same cell signaling and synaptic plasticity processes within the same brain regions as those implicated in other forms of reward learning and memory (Berke and Hyman 2000;Hyman and Malenka 2001;Nestler 2001).The inhibitory control functions of the prefrontal cortical ...

Relapse to cocaine-seeking increases activity-regulated gene expression differentially in the striatum and cerebral cortex of rats following short or long periods of abstinence

“…2b]. Inactive lever pressing was not significantly different during self-administration or testing between cocaine and yoked-saline animals (for details, see Hearing et al 2008).…”

“…2b]. Inactive lever pressing during the 1 h test was significantly greater in animals with a cocaine history compared to yoked-saline treated animals (for details, see Hearing et al 2008). This difference in inactive lever responding likely represents an alternative means of obtaining drug when the lever previously associated with cocaine self-administration no longer provides the drug (Fuchs et al 2006;Berglind et al 2007).…”

“…Details of the self-administration and relapse to cocaine-seeking methodology have been previously described (Hearing et al 2008) for the cohort of rats in experiments 1 and 2 from which the in situ hybridization data in this publication was derived. Only essential behavioral information is provided below to facilitate understanding of the experiments.…”

“…In situ hybridization histochemistry was performed as described previously (Hearing et al 2008) Hearing et al 2008 for sequence details). Twelve μm tissue sections cut through the anterior-posterior extent of the striatum were mounted onto slides and pretreated, hybridized, and washed.…”

“…Quantitation of film autoradiograms was performed using the Macintosh-based NIH Image program as previously described (Wang and McGinty 1995;Hearing et al 2008). The mean density and number of pixels per area were measured in the selected cortical and subcortical areas (Fig.…”