Cue-induced nicotine seeking in rats is associated with SHPS-1 downregulation in the medial prefrontal cortex

Exposure to cues associated with drug taking is a major cause of relapse in humans. The medial prefrontal cortex (mPFC) and the insular cortex are two brain regions that have been strongly implicated in cue-induced relapse to smoking. To increase our understanding of the underlying molecular mechanisms in these areas, we analyzed synaptic protein regulation associated with cue-induced reinstatement after extinction or abstinence from intravenous nicotine selfadmini stration using iTRAQ-based proteomics in rats. After extinction training and forced abstinence, respectively 3 and 51 proteins of 566 detected synaptic proteins were regulated in the mPFC by cue-induced reinstatement. No significant regulation of proteins was observed in the insula. We observed a downregulation of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), a transmembrane protein involved in intercellular communication, in the mPFC upon reinstatement after extinction, which was validated in an independent set of animals. These results confirm the involvement of the mPFC in cue-induced reinstatement of nicotine seeking, potentially entailing a molecular mechanism that involves SHPS-1.