title: Intra-prelimbic cortical inhibition of striatal-enriched tyrosine phosphatase suppresses cocaine seeking in rats.
abstract: Cocaine self-administration in rats results in dysfunctional neuroadaptations in the prelimbic (PrL) cortex during early abstinence. Central to these adaptations is decreased phospho-extracellular signal-regulated kinase (p-ERK), which plays a key role in cocaine seeking. Normalizing ERK phosphorylation in the PrL cortex immediately after cocaine self-administration decreases subsequent cocaine seeking. The disturbance in ERK phosphorylation is accompanied by decreased phosphorylation of striatal-enriched protein tyrosine phosphatase (STEP), indicating increased STEP activity. STEP is a well-recognized ERK phosphatase but whether STEP activation during early abstinence mediates the decrease in p-ERK and is involved in relapse is unknown. Here, we show that a single intra-PrL cortical microinfusion of the selective STEP inhibitor, TC-2153, immediately after self-administration suppressed post-abstinence context-induced relapse under extinction conditions and cue-induced reinstatement, but not cocaine prime-induced drug seeking or sucrose seeking. Moreover, an intra-PrL cortical TC-2153 microinfusion immediately after self-administration prevented the cocaine-induced decrease in p-ERK within the PrL cortex during early abstinence. Interestingly, a systemic TC-2153 injection at the same timepoint failed to suppress post-abstinence context-induced relapse or cue-induced reinstatement, but did suppress cocaine prime-induced reinstatement. These data indicate that the STEP-induced ERK dephosphorylation in the PrL cortex during early abstinence is a critical neuroadaptation that promotes relapse to cocaine seeking and that systemic versus intra-PrL cortical inhibition of STEP during early abstinence differentially suppresses cocaine seeking.
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Ben M
authors.identifier: 0000-0002-6105-6054
authors.initials: BM
authors.lastname: Siemsen
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Jacqueline F
authors.identifier: 0000-0002-6620-0107
authors.initials: JF
authors.lastname: McGinty
mesh_terms: D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases; D008297:Male; D010750:Phosphoproteins; D017397:Prefrontal Cortex; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
chemical_list: C559038:8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine; D001582:Benzothiepins; D018765:Dopamine Uptake Inhibitors; D010750:Phosphoproteins; D048049:Extracellular Signal-Regulated MAP Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C489931:Ptpn5 protein, rat; D003042:Cocaine
keywords: STEP; TC-2153; cocaine; extracellular signal-regulated kinase; prelimbic cortex; self-administration