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 time point 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.

Amperometric measurements of cocaine cue and novel context‐evoked glutamate and nitric oxide release in the nucleus accumbens core

“…Rats in experiment 1 were secured in a stereotaxic apparatus (David Kopf Instruments, model 942) and received a bilateral intra‐prelimbic (PL) cortical (AP: +2.8 mm, ML: ±0.6 mm, DV: −3.8 mm relative to bregma) microinjection of either a chemogenetic or reporter‐only control vector (see materials). Rats in experiments 2 and 4 received a chronic indwelling jugular silastic catheter surgery as described previously (Siemsen, Giannotti, et al, ; Siemsen, Lombroso, & McGinty, ; Siemsen et al, ), and received a single intravenous infusion of Cefazolin to prevent bacterial infection. All rats received a unilateral intra‐NAcore guide cannula (BASi, Catalog number #7030; Pinnacle Technology) implantation following 4 weeks of virus expression (Experiment 1), immediately following catheterization (Experiment 2), in lieu of catheterization (Experiment 3), or 24 hr following the final cocaine SA session (Experiment 4, see below).…”

Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in A2A Receptor-Mediated Effects in the Central Nervous System

“…However, in condition of chronic cocaine consumption, such as in models of cocaine self-administration, a decrease in STEP phosphorylation and pERK1/2 are observed in the rat prefrontal cortex, that could represent early events in withdrawal mechanisms (Sun et al, 2013). More recently, cocaine-induced STEP activation has been demonstrated in the early phase of abstinence, which mediates the decrease in p-ERK observed in the pre-limbic cortex of cocaine-seeking rats (Siemsen et al, 2018). These studies demonstrate an active role of STEP in cocaine-mediated effects.…”

“…In addition, the stimulation of synaptic or extrasynaptic NMDA receptors differently impacts on STEP expression, resulting in the activation of ERK1/2 or p38 MAPK, respectively, and promoting cell survival or death (Xu et al, 2009). Another well identified role for STEP is the modulation of the effects of psychostimulant drugs such as cocaine and amphetamine (Valjent et al, 2005;Hopf and Bonci, 2009;Sun et al, 2013;Siemsen et al, 2018). As for cocaine effects, initial studies demonstrated that following acute cocaine treatment in mice, the increase in ERK1/2 phosphorylation (pERK1/2) in a subpopulation of dopamine D1R-containing striatal neurons was mediated, at least in part, by D1R-mediated STEP inactivation (Valjent et al, 2005).…”

Amperometric measurements of cocaine cue and novel context-evoked glutamate and nitric oxide release in the nucleus accumbens core

“…Rats in experiment 1 were secured in a stereotaxic apparatus and received a bilateral intra-PL cortical (AP: +2.8mm, ML: +/-0.6mm, DV: -3.8 mm relative to bregma) microinjection of either a chemogenetic or reporter-only control vector (see materials). Rats in experiments 2 and 4 received a chronic indwelling jugular silastic catheter surgery as described previously (Siemsen et al 2018a;Siemsen et al 2018b;Siemsen et al 2019), and received a single intravenous infusion of Cefazolin to prevent bacterial infection. All rats received a unilateral intra-NAcore guide cannula implantation following 4 weeks of virus expression (Experiment 1), immediately following catheterization (Experiment 2), in lieu of catheterization (Experiment 3) or 24 hours following the final cocaine SA session (Experiment 4, see below).…”