Role of Src Family Kinases in BDNF-Mediated Suppression of Cocaine-Seeking and Prevention of Cocaine-Induced ERK, GluN2A, and GluN2B Dephosphorylation in the Prelimbic Cortex

Abstract

Models of relapse have demonstrated that neuroadaptations in reward circuits following cocaine self-administration (SA) underlie reinstatement of drug-seeking. Dysregulation of the pathway from the prelimbic (PrL) cortex to the nucleus accumbens is implicated in reinstatement. A single BDNF infusion into the PrL cortex following a final cocaine SA session results in attenuation of reinstatement of cocaine-seeking. Inhibiting BDNF's receptor, TrkB, ERK/MAP kinase activation, or NMDA receptors blocks this attenuating effect, indicating that the interaction between glutamate-mediated synaptic activity and TrkB signaling is imperative to BDNF's suppressive effect on drug-seeking. Src family kinases (SFKs) are involved in both NMDA-mediated activation of TrkB- and TrkB-mediated tyrosine phosphorylation of NMDA receptors. We hypothesized that infusion of the SFK inhibitor, PP2, into the PrL cortex prior to a BDNF infusion, immediately after the end of the last cocaine SA session, would block BDNF's ability to suppress reinstatement of cocaine-seeking in rats with a cocaine SA history. PP2, but not the negative control, PP3, blocked BDNF's suppressive effect on context-induced relapse after 1 week of abstinence and cue-induced reinstatement after extinction. As previously reported, infusion of BDNF into the PrL cortex blocked cocaine SA-induced dephosphorylation of ERK, GluN2A, and GluN2B-containing receptors. Inhibition of SFKs using PP2 blocked BDNF-mediated phosphorylation of GluN2A, GluN2B, and ERK. These data indicate that SFK activity is necessary for BDNF-mediated suppression of cocaine-seeking and reversal of cocaine-induced dephosphorylation of key phosphoproteins in the prefrontal cortex related to synaptic plasticity.

Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core

“…This evidence extends previous data from our laboratory showing that cocaine SA leads to a decrease in phospho-protein signaling in the PrL cortex during early withdrawal (Sun et al 2013; Whitfield et al 2011; Go et al 2016; Barry and McGinty 2017) and extends the findings specifically to PrL-NA core neurons.…”

“…Although there was no significant effect of early withdrawal from cocaine SA on global Fos-IR or pCREB-IR in the nucleus of PrL-NA core neurons during early withdrawal from cocaine SA, there was a significant decrease in Fos-IR and pCREB-IR selectively in the nucleus of PrL-NA core neurons. This evidence extends previous data from our laboratory showing that cocaine SA leads to a decrease in phospho-protein signaling in the PrL cortex during early withdrawal (Sun et al 2013; Whitfield et al 2011; Go et al 2016; Barry and McGinty 2017) and extends the findings specifically to PrL-NA core neurons.…”

Mechanisms underlying the efficacy of exercise as an intervention for cocaine relapse: a focus on mGlu5 in the dorsal medial prefrontal cortex

“…As discussed above, one possible explanation is that there are multiple, possibly redundant, mechanisms underlying the efficacy of exercise to reduce relapse-like responding. For example, intra-dmPFC BDNF infusion during early abstinence prevents the incubation of cocaine-seeking and this mechanism appears to be mediated by TrkB activation of Src family kinases (SFKs) and the subsequent phosphorylation of GluN2 subunits of NMDA receptors (Barry and McGinty 2017). SFKs act as a convergence point for many signaling pathways to regulate NMDA receptor activity, and one of the most well characterized pathways upstream of SFKs are G-protein coupled receptors including mGlu5 (Salter and Kalia 2004).…”

Accumbens brain‐derived neurotrophic factor (BDNF) transmission inhibits cocaine seeking

“…; Li et al , 2015). A single BDNF injection into the PFC activates the ERK signaling pathway, changes the phosphorylation of NMDA receptors in the PL by activating Src family kinases (Barry & McGinty ) and produces enduring inhibition through normalizing cocaine‐mediated extracellular glutamate spillover in the NAcc (Berglind et al . ).…”